key: cord-1009903-tc2us2qy
authors: Yin, Jialing; Li, Chengcheng; Ye, Chunhong; Ruan, Zhihui; Liang, Yicong; Li, Yongkui; Wu, Jianguo; Luo, Zhen
title: Advances in the development of therapeutic strategies against COVID-19 and perspectives in the drug design for emerging SARS-CoV-2 variants
date: 2022-01-31
journal: Comput Struct Biotechnol J
DOI: 10.1016/j.csbj.2022.01.026
sha: 0ebfa817d611392b6e100e78befae5174ffc3f78
doc_id: 1009903
cord_uid: tc2us2qy

Since Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was identified in late 2019, the coronavirus disease 2019 (COVID-19) pandemic has challenged public health around the world. Currently, there is an urgent need to explore antiviral therapeutic targets and effective clinical drugs. In this study, we systematically summarized two main therapeutic strategies against COVID-19, namely drugs targeting the SARS-CoV-2 life cycle and SARS-CoV-2-induced inflammation in host cells. The development of above two strategies is implemented by repurposing drugs and exploring potential targets. A comprehensive summary of promising drugs, especially cytokine inhibitors, and traditional Chinese medicine (TCM), provides recommendations for clinicians as evidence-based medicine in the actual clinical COVID-19 treatment. Considering the emerging SARS-CoV-2 variants greatly impact the effectiveness of drugs and vaccines, we reviewed the appearance and details of SARS-CoV-2 variants for further perspectives in drug design, which brings updating clues to develop therapeutical agents against the variants. Based on this, the development of broadly antiviral drugs, combined with immunomodulatory, or holistic therapy in the host, is prior to being considered for therapeutic interventions on mutant strains of SARS-CoV-2. Therefore, it is highly acclaimed the requirements of the concerted efforts from multi-disciplinary basic studies and clinical trials, which improves the accurate treatment of COVID-19 and optimizes the contingency measures to emerging SARS-CoV-2 variants.

The new coronavirus, namely 2019-nCoV, was first identified on December 31, 2019. Due to being highly homologous to Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), 2019-nCoV was listed as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) by the International Commission for Classification of Viruses (ICTV) on February 11, 2020 [1] . Among seven coronaviruses infecting humans, three coronaviruses can cause serious diseases, including severe acute respiratory syndrome coronavirus (SARS-CoV) emerging in 2003, Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in 2019 [2] .

The outbreak of SARS-CoV-2 causes an acute respiratory disease called coronavirus disease 2019 and leads to a severe epidemic worldwide. Typical symptoms of COVID-19 include fever, sore throat, fatigue, cough, and difficulty breathing [3, 4] . Some of the clinical symptoms are similar to those of respiratory infections and cannot be accurately diagnosed. The approach to quickly diagnose and develop related drugs and vaccines has become a top priority. At present, the WHO has approved the use of a variety of vaccines [5] .

As of January 9, 2022, the cumulative number of reported cases worldwide has exceeded 304 million, and the cumulative death toll has been more than 5.4 million [6] . As of January 13, 2022, a total of 9.2 billion doses of vaccine have been administrated globally ( Figure 1 ).

Till now, there have been candidate drugs in COVID-19 treatment at different stages and levels available for selection and further research and development (Table 1 ). These smallmolecule drugs can exert therapeutic effects against COVID-19 by preventing SARS-CoV-2 from entering cells, inhibiting viral proteases or RNA-dependent RNA polymerase activities, reducing virus-induced inflammation, and balancing immunomodulatory effect in host [7, 8] .

Fortunately, some antiviral drugs have been used in clinical practice and play certain roles in the treatment of COVID-19 patients, such as Remdesivir and Molnupinavir [9] [10] [11] . Currently, hundreds of clinical trials of COVID-19 drugs are underway to obtain satisfactory clinical results [12] . A large number of promising clinical trials will determine which drugs or vaccines are suitable for the treatment or prevention of COVID-19 (Table 2) .

1ab is translated through ORF1ab in viral genome, and subsequently cleaved into 16 nonstructural proteins by protease ( Figure 2B ).

The proteins of SARS-CoV-2 are highly glycosylated [20] . For example, about 40% surface of S protein is covered by glycans [21] , which helps the virus hide epitopes and avoid antibody recognition [22] . SARS-CoV-2 S protein comprises 22 N-linked glycosylation sequons per protomer [23] . Because glycosylation is the key to virus invasion, the glycosylation of S protein needs to be taken into consideration when designing vaccines and antibodies [24] .

SARS-CoV-2 can bind to Angiotensin-converting enzyme 2 (ACE2), a functional receptor of SARS-CoV [25] , on the cell surface with its S protein to enter the cell through membrane fusion and endocytosis [19] ( Figure 3A ). Proteins from host cells, such as the serine protease TMPRSS2 [26] and high-density lipoprotein (HDL) scavenger receptor type B (SR-B1) [27] , facilitate the SARS-CoV-2 invasion processes ( Figure 3B ). Transmembrane serine protease 4 (TMPRSS4) is found to be most significantly related to ACE2 [28] . SARS-CoV-2 has its unique Furin cleavage site never found before in other coronaviruses, is required for the virus to enter cells lacking cathepsin protease [29] . Furin can cleave the SARS-CoV-2 spike protein at the S1/S2 site [2] , resulting in active S1 and S2 subunits. The cutting process occurs during the virus packaging process [30] .

Once entering the host cell, the virus particle releases the viral genome, and utilizes host ribosome to translate the viral polyproteins pp1a and pp1ab [31] . Then the viral protease 3CLpro [32] and PLpro [33] cleave the polyprotein into a variety of active proteins ( Figure 3C ). Viral replication is dominated by a replication/transcription complex composed of nonstructural proteins [34] . For example, nsp7, nsp8, and nsp12 together form the virusindependent RNA polymerase structure (RdRp) for viral genome replication [35] ( Figure 3D ).

The translation of nsp14 can shut down the host protein synthesis and inhibit the innate immune response, while the combination of nsp10 enhances this effect [36] .

After four structural protein is produced by transcription, the N protein binds to the genome, and the remaining three (S, E, and M) are integrated into the endoplasm and then sent to the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) for further process, such as furin-mediated cleavage. Subsequently, the assembled progeny virus was released by exocytosis or budding [37, 38] for the next round of invasion to host cell ( Figure 3E ). In ERGIC, E protein can form pores to cause Ca 2+ to leak and activate NLRP3 inflammasome to achieve pro-inflammatory effects [39] ( Figure 3F ).

The process of SARS-CoV-2 entering the human body and self-replicating to release progeny virus can be divided into different stages. According to the characteristics of each dynamic stage, different drug targets to these specialized processes are formulated to block the life activities of the virus (Figure 3 ).

Alpha-1 antitrypsin (α1AT) inhibits the protease activity of TMPRSS2 at physiological concentrations to restrain the entry and replication of SARS-CoV-2 in cell lines and primary cells [40] . A statistical study based on 500,000 people shows that mild α1-Antitrypsin deficiency (AATD) genotypes were not associated with increased SARS-CoV-2 infection rates or fatalities [41] . For the lack of α1AT makes it easier to activate TMPRSS2, severe AATD patients may be susceptible to SARS-CoV-2 [42, 43] . There have been four trials recruited or completed to test whether α1AT can be used for the treatment of COVID-19 patients [44].

Halofuginone can reduce endogenous TMPRSS2 expression at sub-micromolar concentrations, which showed significant resistance to SARS-CoV-2 infection in vitro in both live-and pseudo-virus models [45] . Halofuginone is an oral anti-fibrosis [46] and antiinflammatory [47] drug. A study in mice reveals that the distribution of halofuginone can be detected in various organs, including kidneys and lungs [48] . ACE2 is widely expressed in these organs [49] , making these organs vulnerable to the SARS-CoV-2. Therefore, the antiviral activity and wide distribution of halofuginone in vivo repurpose it as a promising anti-SARS-CoV-2 drug.

Platycodon grandiflorum D (PD), a natural component of Platycodon grandiflorum [50] , and pan-coronavirus fusion inhibitor EK1 derived lipopeptide EK1C4 [51] can effectively block SARS-CoV2-mediated membrane fusion to combat viral infections. Since TMPRSS2 is induced by androgens (AR), the AR anti-caking agent Proxalutamide (GT0918) can significantly accelerate virus clearance on day 7 in patients with mild to moderate COVID-19 [52] .

Catechin and curcumin have a strong binding affinity to the virus S protein and host receptor ACE2 and its complex, which can trigger local structural fluctuations of the protein through their binding with RBD/ACE2 complex [53] . In a study, using protein engineering technology, the self-assembled tetramerization domain from p53 protein produces a super tetravalent form of ACE2 coupled to the Fc region of human immunoglobulin γ1, the high-molecular-weight Quad protein (ACE2-Fc-TD) retains the binding to the ACE2 and its binding SARS-CoV-2 S protein and can form a complex with the S protein and antiviral antibodies as a bait protein [54] . Similarly, antibodies that bind to viral RBD epitopes (such as REGE-CoV) [55, 56] or that target the ACE2 receptor (such as h11B11) [57] can also effectively prevent and reduce the symptoms of viral infections. The viral load in the SARS-CoV-2 infected animals is significantly reduced after the single-dose h11B11 treatment, while the animals showed less interstitial pneumonia and limited pathological features under the preventive treatment conditions [57] , which makes it a potential therapeutical agent in COVID-19.

The organic selenium compound Ebselen and its structural analogs can inhibit the activity of the SARS-CoV-2 protein PLpro in the nanomolar range [45] . Two clinical trials of Ebselen are now recruiting moderate and severe COVID-19 patients [44] . There is also evidence that Catechin binds to the S1 ubiquitin-binding site of PLpro, which may inhibit its protease function and cancel the inhibitory function of SARS-CoV-2 on the ubiquitin-proteasome system and the interferon-stimulated gene system [58] .

The viral main protease Mpro is also a widely explored drug target. Two kinds of small molecule compounds with indole structure named GRL-1720 and 5h inhibit the main protein Mpro of the SARS-CoV-2, which can effectively block viral infections in vitro [59] . Another Mpro inhibitor, GC-376, is also a promising main candidate for further development of the treatment of SARS-CoV-2 infection [60] . GC-376 exhibits no toxicity in K18-hACE2 mice experiment, showing moderate benefits in terms of clinical symptoms, weight change, and survival rate. Under low-dose virus attack, GC-376 can prevent the virus from reaching the brain and reduce inflammatory cell distribution and virus staining [60] . However, the potential anti-inflammatory effect needs to be further developed.

The active form of Remdesivir, which has been approved for COVID-19 treatment, acts as a nucleoside analog [61] and inhibits RNA-dependent RNA polymerase (RdRp). Remdesivir is incorporated into the growing RNA product by RdRp [62] , and the translocation barrier causes RNA 3'-nucleotide to remain at the substrate binding site of RdRp and interfere with the entry of the next nucleoside triphosphate, thereby stagnating RdRp [63] . Multiple trials have confirmed the effectiveness of Remdesivir treatment [64, 65] . Through binding to viral RdRp, other nucleoside analogs such as Ribavirin, Sofosbuvir, Galidesivir, Setrobuvir, and Tenofovir behave as potent drugs against SARS-CoV-2 [66, 67] . Nevertheless, it is still a long way for these FDA-approved RdRp inhibitors to apply in COVID-19 from bench to bed.

So far, it has always been the top priority of scientists to find a convenient, effective, and low-cost oral drug against COVID-19 because of the expensive monoclonal antibodies. On December 22, 2021, the FDA issued an emergency use authorization for Pfizer's Paxlovid, and on the following day, it urgently approved Merck's Molnupiravir [68] . Paxlovid is composed of Nimarivir (PF-07321332) and low-dose Ritonavir. Pfizer claims that compared with placebo treatment group, the risk of hospitalization or death in non-hospitalized adults at high risk of COVID-19 treated with Paxlovid was reduced by 89%. Nimarivir is a SARS-CoV-2 3CLpro inhibitor and can reduce virus replication [69] . Ritonavir can alleviate the degradation of Nimarivir and keep it at a higher concentration for a long duration as possible [70] . Recently, the oral antiviral drug Molnupiravir, an inhibitor of RdRp leading to viral fatal mutations or premature termination of replication [71] , has attracted attention and expectation. Although

Molnupirivir is reported host mutation activity in animal cell culture experiments [72] , the safety of molnupiravir was confirmed in a drug safety assessment [73] .

The assembled progeny of SARS-CoV-2 is released by exocytosis or budding [37, 38] .

Oseltamivir is a prodrug against neuraminidase inhibitor, which has been approved for the treatment and prophylaxis of influenza A by inhibiting the release of progeny virion by budding from the infected cells [74] . In both in vitro and in vivo studies, Oseltamivir is ineffective against SARS-CoV-2 and fails to improve the patients' symptoms and signs in the clinic [75] .

ACE2-positive neighboring cells. The expression of SARS-CoV-2 S protein in the absence of any other viral proteins triggers the formation of syncytia [76] and determines syncytiummediated lymphocyte elimination [77] . The anti-helminth drug Niclosamide was found to significantly reduce the calcium oscillation and membrane conductance in cells expressing spikes [78] , which interferes with the syncytial formation process induced by S protein. A trial proved that Niclosamide has relatively safe clinical benefits in COVID-19 management.

Compared with the control group, the cure rate of the Niclosamide treatment group increased [79] . Niclosamide has poor oral bioavailability due to its limited water solubility. Therefore, considering the economic issues of treatment, it is necessary to explore its effective use.

Inflammation is an early response triggered by harmful stimuli and conditions to restore homeostasis. SARS-CoV-2 could evoke the immune system and induce pro-inflammatory factors such as IL-6, IL-1, TNF-α, and IFN [80] [81] [82] overproduction called a cytokine storm, which brings catastrophic damage to cells and then causes dysfunction and failure of tissues and organs [83] . The levels of cytokines in critical COVID-19 patients are significantly higher than those in mild conditions [84] . SARS-CoV-2 infection can cause cytokine release syndrome (CRS) [85] , which then produces a series of consequences such as multiple organ dysfunction syndrome (MODS), acute respiratory distress syndrome (ARDS), and even death [86] [87] . The intervention and treatment of cytokine storm are necessary means to reduce COVID-19 mortality (Figure 4 ).

Overdose of interleukin-6(IL-6)is one of the causes of cytokines storm in COVID-19 [88] .

Tocilizumab (TCZ) is the first IL-6 receptor inhibitor discovered, which reduces the immune damage caused by IL-6 to target cells by competitively binding to IL-6 receptors [89] . Shreds of evidence have shown that in a limited number of patients, symptoms, hypoxemia, and changes in chest tomography (CT) opacity in patients treated with TCZ are immediately improved [90] . Results from a primary intention-to-treat (ITT) phase 2 population shows that TCZ may reduce lethality rates at 30 days [91] . In a meta-analysis, however, there was no difference in mortality between the TCZ treatment group and the placebo group. TCZ can reduce the length of hospital stay while the impact on survival has not been statistically proven, but the combined use of corticosteroids is found enable to optimize the proven effectiveness of corticosteroids [92] . Hence, to better use TCZ in COVID-19 treatment, the combination of medication can be taken into consideration.

Anakinra is a recombinant interleukin-1 (IL-1) receptor antagonist with anti-inflammatory and immunomodulatory effects [93] . A study has revealed that Anakinra significantly reduces the mortality and the ICU invasive mechanical ventilation needs of COVID-19 patients [94] .

An updated meta-analysis shows that Anakinra can reduce the 50% risk of death in hospitalized patients with moderate to severe COVID-19 compared with patients untreated with Anakinra [95] . Chloroquine owns an immunomodulatory effect, inhibiting the production and release of TNF-α and IL-6 [96] , which may modulate cytokine storm in COVID-19 [97, 98] . However, it has not been shown to benefit COVID-19 patients in randomized controlled trials [99] .

Sarilumab is another IL-6 blocker [100, 101] , a fully human immunoglobulin G1 monoclonal antibody with a high affinity for membranes and IL-6 receptors [102] . A retrospective case from an institution in southern Italy showed that 10 COVID-19 patients (67%) observed rapid improvement in their respiratory parameters after using Sarilumab [103] . In the results of the Sarilumab at a safe dose of 400 mg and placebo groups, the COVID-19 patient mortality rates were 23% and 27%, while the hospital discharge rates were 53% and 41%, respectively [102] .

Canakinumab is an IL-1 blocker developed by Novartis for the treatment of inflammatory diseases [104] . In a study of 48 patients with moderate COVID-19-related pneumonia, Canakinumab was found to reduce the need for invasive mechanical ventilation. 63% of patients in the Canakinumab group were discharged within 21 days while the control group was 0% [105] . For mild or severe COVID-19 pneumonia, a study has observed a decrease in the inflammation index in the Canakinumab group, which can lead to a rapid and lasting improvement in oxygenation levels [106] .

With IL-12 or IL-15, IL-8 can be an effective inducer of IFN-γ in certain kinds of cells [107] . The combination of TNF-α and IFN-γ can strongly induce cell death characterized by inflammatory cell death [108] . In COVID-19 patients, these uncontrolled expressions of cytokines can cause excessive damage to tissues and organs [109] . As a result, inhibitors of abnormally increased levels of cytokines can be used as potential drugs for COVID-19 treatment. Meanwhile, due to the existence of synergistic effects, combination drugs or multitargets can be considered view of drug development. However, the combinate use of corticosteroids is still controversial. While inhibiting inflammation, it also stops the elimination of the virus and causes a series of side effects [110, 111] .

Janus Kinase (JAK)-Signal Transducer and Activator of Transcription (STAT) pathway is essential for the development and function of the immune system [112] , which are involved in the various pro-inflammatory factors [113] . Therefore, the use of JAK inhibitors is one of the ideas to reduce the cytokine storm in COVID-19. Baricitinib and Ruxolitinib are potent and selective JAK inhibitors approved for indications such as rheumatoid arthritis and myelofibrosis [114] , which are currently reused for the treatment of SARS-CoV-2 infected patients. Studies have confirmed the safety and effectiveness of these drugs in reducing cytokine levels in the treatment of COVID-19 as antiviral drugs [115] [116] [117] . In addition, Baricitinib has the effect of reducing the endocytosis of the SARS-CoV-2 [118] . The combined use of Baritinib and Remdesivir can shorten the recovery time and accelerate the improvement of clinical status, especially for patients receiving high-flow oxygen or non-invasive ventilation [119] .

The nuclear factor NF-κB pathway is a classic pro-inflammatory signaling pathway [120] .

The inhibition of NF-κB signaling has therapeutic applications in cancer and inflammatory diseases [121] , as well as virus-and LPS-induced cytokine storms [122] . The use of NF-κB inhibitors Caffeic acid phenethyl ester (CAPE) and Parthenolide can improve the survival rate of mice infected with SARS-CoV [123] . Considering the spike protein of coronavirus upregulates IL-6 and TNF-α in murine macrophages through the NF-κB pathway [124] , the exploration of NF-κB inhibitors may be an effective measure to reduce the cytokine storm upon SARS-CoV-2 infection. Although some studies have found potential new drugs that can be used to inhibit NF-κB to inhibit SARS-CoV-2 infection, [125, 126] , whether they can be applied to the treatment of COVID-19 remains to be investigated.

In a trial to screen drugs with SARS-CoV-2-related pangolin coronavirus model, the Cepharanthine (CEP) showed a significant antiviral effect [127] . CEP inhibits viral replication by modulating signaling pathways [128, 129] , among which it exhibits anti-inflammatory effects through AMPK activation and NF-κB inhibition [130] . Another study also confirmed the antiviral effect of CEP, and the combination of CEP and Nelfinavir can enhance their efficacy [131] . Existing evidence shows that CEP has important potential value in the treatment of COVID-19 [132] , it still needs further verification by in vivo experiments and clinical trials.

Pidotimod is a synthetic dipeptide molecule, which has biological and immunological activity on both the adaptive and the innate immune responses [133] . Pidotimod can increase the expression of NF-κB protein without an increase of IL-8 expression [134] . Pidotimod has been evaluated as an immunostimulant for respiratory infections (RTIs) [135] and the treatment of many other diseases [136] . A controlled experiment involving 20 COVID-19 patients showed that Pidotimod can effectively improve the fever of patients and prevent the activation of the cytokine cascade [137] . Viral infections usually cause excessive hyperinflammation [138] . The anti-inflammatory effect of steroids can stabilize hemodynamics and shorten the stay time of the intensive care unit (ICU) and the duration of mechanical ventilation. The use of steroids has always been controversial. Steroids can significantly reduce anti-inflammatory factors and may also delay virus clearance [139] . Long-term use of steroids can cause many adverse events, such as secondary infections [140] . In addition, The correlation between steroids and mortality remains unclear [141] . Steroids are currently used in critically ill patients to reduce clinical deterioration.

One meta-analysis shows that the use of steroids is associated with higher mortality [142] , whereas another prospective meta-analysis of seven randomized trials showed that the use of systemic corticosteroids was associated with lower all-cause mortality from COVID-19 [143] .

The contradictory results indicate that there is still uncertainty in the role of corticosteroids, and more randomized controlled trials are needed to prove its effectiveness.

It is undeniable that corticosteroids have been widely used in the treatment of severe COVID-19 cases [144] . A trial showed that the 28-day mortality is reduced in COVID-19 patients receiving respiratory support after receiving up to ten days of dexamethasone treatment, which is useless for patients who do not require respiratory support [145] . The use of cedemethasone can reduce lung damage in COVID-19 patients [146] , which is recognized by WHO in the clinical trial [147] . Whether other steroids have the same effects as dexamethasone is still unknown [148] . The combination of other drugs may alleviate the side effects of steroid use. An observational cohort study found that the combination of Barectinib and corticosteroids in the COVID-19 treatment can significantly improve lung function compared with corticosteroids alone [149] . Nonetheless, how to maximize the drug effect with a lower dose and shorter treatment time is another urgent problem that needs to be solved.

Rehabilitation plasma therapy can be taken in the early stage of COVID-19 by using antibodies in the convalescent serum to neutralize the virus to reduce the body damage caused by the immune system [150] . After the occurrence of cytokine storm, patients will have a variety of symptoms, such as MODS and ARDS. At this stage, anti-shock treatment is required to maintain the patient's body homeostasis and protect important organ functions.

In addition to conventional treatment, traditional Chinese medicine (TCM) plays an important role as an auxiliary method in clinical COVID-19 treatment, which has been confirmed to have antiviral activity against various coronavirus strains [151] . TCM treatment can improve clinical efficacy and alleviate COVID-19 patients' severe conditions [152, 153] . In Vero cells, LHQW reduced the mRNA expression of pro-inflammatory cytokines TNFα, IL-6, CCL-2/MCP-1, and CXCL-10/IP-10 [156] . A comparative study of multiple combination medications shows that the quadruple combination with LHQW can be the first choice for the treatment of patients in critical condition [157] . In detail, Rhein, forsythoside A, forsythoside I, neochlorogenic acid and its isomers may be the effective active ingredients of LHQW against SARS-CoV-2 [158] . A retrospective analysis of JHQG treatment promotes the absorption of pneumonia permeate with a higher 7-day viral clearance rate compared with the control group [159] . HSBD is suitable for early COVID-19 treatment [160] , while XBJ is mainly used for patients in critical conditions [161] . The XBJ may relieve systemic inflammation by inhibiting the secretion of pro-inflammatory cytokines mediated by the HMGB1/RAGE axis to reduce mortality [162, 163] . pandemic. Notably, the standardization behind different kinds of traditional Chinese medicines with various functions is highlighted and needs to be concerned.

SARS-CoV-2 has been continuing to evolve, posing higher infectivity efficiency and faster transmission, leading to a greater risk to global public health. To better assess the consequences of different variants and facilitate prevention measures or medical countermeasures, WHO divides them into variants of interest (VOI) and variants of concern (VOC) [164] . There are currently two VOIs: Kappa and Mu; and five VOCs: Alpha, Beta, Gamma, Delta, and Omicron (Table 3) . On November 24, 2021, a new SARS-CoV-2 variant B.1.1.529 named Omicron was discovered in South Africa. Previously, the SARS-CoV-2 Delta variant has become the main epidemic strain in many countries [165] . Now, the emergence of omicron has aroused new attention and vigilance. The mutations in Omicron are concentrated in the S protein, and there seems to be a tendency to collect mutations that are beneficial to immune escape [166, 167] . A model predicts and calculates that Omicron's infectivity is about ten times that of the original virus or twice that of the Delta variant. Omicron may greatly undermine the efficacy of the Eli Lilly monoclonal antibody (mAb) approved by the FDA, and may also reduce the efficacy of mAbs from Celltrion and Rockefeller University [168] . The main SARS-CoV-2 variants reported in different places worldwide create new concerns about anti-viral drugs and vaccinations against COVID-19 pandemic ( Figure 5 ). The following critical mutation sites in SARS-CoV-2 genome determine the virulence and spread of the SARS-CoV-2 (Table 4) , which provides fresh ideas in the drug design for the main emerging variants.

D614G mutation in S protein will not significantly change the neutralizing properties of antibodies against SARS-CoV-2, and the currently developed vaccine against wildtype is still effective against the D614G strain [169] . The presence of the E484K mutation located in the receptor-binding domain (RBD) of the S protein will reduce the neutralizing power of a variety of effective mAbs that change the receptor-binding motif on RBD [170] . The introduction of E484K mutations into other variant strains will also lead to a decrease in the neutralization of antibodies and monoclonal antibodies caused by the vaccine [171] . N501Y mutation found in the British variant strain B.1.1.7 has almost no effect on the neutralizing effect of neutralizing nanobodies (Nbs) [172] . However, the mutant strain often accompanies other key amino acid mutations that affect the binding of S protein to ACE2. L18F mutation occurs in the NTD region and can cancel the binding of S2L28 monoclonal antibody to NTD [173] and the L18F mutation is positively correlated with mortality [174] . K417N mutation, close to the ACE2 binding site, is slightly detrimental to ACE2 binding [171] , but it can promote the process of variants effectively avoiding antibodies by eliminating the buried interface salt bridge between RBD and neutralizing antibody CB6 [175] . L452R mutation locates in the RBD hydrophobic plaques of the spike protein [176] . It will increase the affinity of the spike protein to ACE2 and is kind of destructive to NAb binding [177] and make the virus evade the monoclonal antibody LY-CoV555 [178] . P681R is a mutation near the furin-cleavage site [179] , which enhances the cleavage of S1 and S2 by the full-length spike, resulting in increased infection through the cell surface [180] .

Among the SARS-CoV-2 nonstructural proteins (nsp), virus-associated enzymes such as RdRp and 3C are important drug targets [181] . Mutations at these sites may increase virus resistance to related drugs [182, 183] . Mutations in RdRp, for example, may reduce the effect of Remdesivir. Studies have shown that the 14408 C>T mutation increases the viral mutation rate, while 15324 C>T has a reduced effect [184] . Mutations in nsp may correlate with the degree of symptoms caused by SARS-CoV-2. A study found that mutations located in the nsp6 coding region were significantly associated with asymptomatic COVID-19 [185] , which could make it difficult to initially screen COVID-19 patients. Different nsps have their structures and functions, which can be changed by the mutations [186] . For example, the V121D mutation in nsp1 may have a disruptive effect on it, and the G1691C in Nsp3 reduces the flexibility of the protein [187] . Therefore, these mutations in nsps should be taken into account in drug and vaccine development or treatment against COVID-19.

The current SARS-CoV-2 genome site mutations are all subject to natural selection and drug screening, which reflect the adaptation of the virus to the treatments. Some mutations make the virus increase the infectivity and transmission, however, in terms of treatment, the previous drugs are still effective against SARS-CoV-2 variants [188] . Other mutations render part of the antibody ineffective against SARS-CoV-2 [189] , and the virus escapes from immunity, which brings new challenges to treatment. Therefore, the exploration of broadly antiviral drugs is prior to being concentrated and developed. More importantly, the immunomodulatory and holistic therapy in host, including anti-inflammatory strategies and Chinese traditional medicine treatment, should be concerned in the drug design for SARS-CoV-2 variants.

The binding of SARS-CoV-2 S protein to the ACE2 receptor is a key activity for the virus to invade the human body, and most of the mutation sites that are currently being studied are located in the S protein [190] . Researchers need to test one by one to determine the impact of specific mutation sites on the life of the SARS-CoV-2 and then test whether the previous treatments such as monoclonal antibodies are still effective for the emerging variants. However, a SARS-CoV-2 variant often carries a combination of different mutation sites and becomes a multiple mutant strain, and the speed of mutation is rapid [177] . It is of high concern that the effects from different combinations of mutation sites will have on viral infection activities. As a result, the highly conservative sites of the SARS-CoV-2 genome as drug targets could be paid more attention to maintaining antiviral activities against variants.

SARS-CoV-2 has caused a global pandemic since late 2019. With the increase of experience and knowledge, defensive measures and clinical treatment plans are adopted immediately according to observation and management of COVID-19 pandemic. Meanwhile, researchers are exploring more possibilities of repurposing drugs against SARS-CoV-2 [191] .

However, the development of specific drugs and vaccines requires fundamental studies on SARS-CoV-2, such as the interaction between the virus and the host, the epidemiology and molecular virology, the host immune responses to viral infection, to uncover the mechanism underlying the infection, transmission, and pathogenesis of the virus and explore effective drugs.

Traditional Chinese medicine has played a huge role in China's anti-epidemic process [192] . Research on the mechanism of action of traditional Chinese medicine may provide new ideas for the development of anti-SARS-CoV-2 drugs. At the same time, it is necessary to pullulate holistic treatments to deal with the systemic pathological imbalance caused by the SARS-CoV-2.

Owing to the error-prone RNA replicase of SARS-CoV-2 [193] , the continuous emergence of mutant strains has undoubtedly brought huge difficulties and challenges to the control of the global COVID-19 epidemic. The appearance of SARS-CoV-2 variants means that the virus adapts to manual interventions and natural selection, which may eliminate the effectiveness of previous drugs and vaccines. In this case, we must maintain epidemiological surveillance of COVID-19 timely and focus on the evolution of the virus, especially the emergence of drugresistant strains.

The pathogenesis of COVID-19 can be mainly divided into two phases [194] . In the early stage, the COVID-19 patients may begin with a series of mild symptoms including fever, cough, fatigue, hemoptysis, headache, or diarrhea, and then will develop pneumonia [155, 195] .

Accordingly, antiviral drugs can be given to clear the virus from the body of patients infected with SARS-CoV-2. Later on, as the viral load increases and spreads in the human body, which triggers excessive production of cytokines, a cytokine storm occurs in the COVID-19 patients to deteriorate to moderate and severe symptoms with respiratory distress syndrome and organ failure [196, 197] . It should be necessary to adopt antiviral drugs with immunomodulatory treatment, and also encouraged to introduce holistic therapy and traditional Chinese medicine treatment, and even external mechanical equipment and maintain the normal operation of the patient's body [198] .

In sum, SARS-CoV-2 mutation is an urgent issue that needs to be explored and solved, which requires concerted efforts from the fields of structural biology, medicine, virology, pharmacy, public health, epidemiology, chemistry, and other disciplines, to jointly deal with the treatment and control of COVID-19 pandemic. The entry of SARS-CoV-2 is initiated through that TMPRSS2 acts on the S protein to activate the S1 and S2 subunits. The S1 subunit binds to the ACE2 receptor to occur endocytosis (A), and S2 mediates membrane fusion (B). Subsequently, the virus releases its genomic RNA, The main emerging SARS-CoV-2 variant strains are classified as VOC (variants of concern), VOI (variants of interest), and VUM (variants under monitoring). VOC includes Alpha, Beta, Gamma, Delta, and Omicron; VOI contains Lambda and Mu, while VUM includes Theta, Eta, Iota, and Kappa from the public data (https://outbreak.info/situation-reports#custom-report, as of 26 November 2021). The time of appearance is expressed as yy/mm. 

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COVID-19 Weekly Epidemiological Update

Strategies for Targeting SARS CoV-2: Small Molecule Inhibitors-The Current Status

Therapeutic targets and interventional strategies in COVID-19: mechanisms and clinical studies

Candidate drugs against SARS-CoV-2 and COVID-19

Simultaneous quantification of seven repurposed COVID-19 drugs remdesivir (plus metabolite GS-441524), chloroquine, hydroxychloroquine, lopinavir, ritonavir, favipiravir and azithromycin by a two-dimensional isotope dilution LC-MS/MS method in human serum

Molnupiravir, an Oral Antiviral Treatment for COVID-19, medRxiv

A Minireview of the Promising Drugs and Vaccines in Pipeline for the Treatment of COVID-19 and Current Update on

SARS-CoV-2 variant prediction and antiviral drug design are enabled by RBD in vitro evolution

Reduced neutralization of SARS-CoV-2 B.1.617 by vaccine and convalescent serum

A structural analysis of M protein in coronavirus assembly and morphology

The coronavirus nucleocapsid is a multifunctional protein

Coronavirus envelope protein: current knowledge

Synthesis and characterization of a native, oligomeric form of recombinant severe acute respiratory syndrome coronavirus spike glycoprotein

Mechanisms of coronavirus cell entry mediated by the viral spike protein

The glycosylation in SARS-CoV-2 and its receptor ACE2

Analysis of the SARS-CoV-2 spike protein glycan shield reveals implications for immune recognition

Vulnerabilities in coronavirus glycan shields despite extensive glycosylation

Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein

Glycosylation is a key in SARS-CoV-2 infection

Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus

Recent Developments on Therapeutic and Diagnostic Approaches for COVID-19

HDL-scavenger receptor B type 1 facilitates SARS-CoV-2 entry

SARS-CoV-2 receptor ACE2 is co-expressed with genes related to transmembrane serine proteases, viral entry, immunity and cellular stress

Comparison of Severe Acute Respiratory Syndrome Coronavirus 2 Spike Protein Binding to ACE2 Receptors from Human, Pets, Farm Animals, and Putative Intermediate Hosts

Cell entry mechanisms of SARS-CoV-2

Processing of the human coronavirus 229E replicase polyproteins by the virus-encoded 3C-like proteinase: identification of proteolytic products and cleavage sites common to pp1a and pp1ab

Characterization of a human coronavirus (strain 229E) 3C-like proteinase activity

Identification of severe acute respiratory syndrome coronavirus replicase products and characterization of papain-like protease activity

SARS-CoV-2: Structure, Biology, and Structure-Based Therapeutics Development

Structure of replicating SARS-CoV-2 polymerase

Translational shutdown and evasion of the innate immune response by SARS-CoV-2 NSP14 protein

Morphogenesis and cytopathic effect of SARS-CoV-2 infection in human airway epithelial cells

SARS-CoV-2 Infections and ACE2: Clinical Outcomes Linked With Increased Morbidity and Mortality in Individuals With Diabetes

Severe acute respiratory syndrome coronavirus E protein transports calcium ions and activates the NLRP3 inflammasome

Mechanisms of SARS-CoV-2 Transmission and Pathogenesis

SARS-CoV-2 infection in alpha1-antitrypsin deficiency

alpha1-Antitrypsin deficiency and the risk of COVID-19: an urgent call to action

Alpha-1 antitrypsin deficiency severity and the risk of COVID-19: A Portuguese cohort

Identification of ebselen and its analogues as potent covalent inhibitors of papain-like protease from SARS-CoV-2, Sci Rep

The Prolyl-tRNA Synthetase Inhibitor Halofuginone Inhibits SARS-CoV-2 Infection, bioRxiv

Halofuginone -the multifaceted molecule

Pharmacokinetics and tissue distribution of halofuginone (NSC 713205) in CD2F1 mice and Fischer 344 rats

The pivotal link between ACE2 deficiency and SARS-CoV-2 infection

Platycodin D, a natural component of Platycodon grandiflorum, prevents both lysosome-and TMPRSS2-driven SARS-CoV-2 infection by hindering membrane fusion

Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion

Proxalutamide Significantly Accelerates Viral Clearance and Reduces Time to Clinical Remission in Patients with Mild to Moderate COVID-19: Results from a Randomized

Catechin and curcumin interact with S protein of SARS-CoV2 and ACE2 of human cell membrane: insights from computational studies

A super-potent tetramerized ACE2 protein displays enhanced neutralization of SARS-CoV-2 virus infection

The monoclonal antibody combination REGEN-COV protects against SARS-CoV-2 mutational escape in preclinical and human studies

Subcutaneous REGEN-COV Antibody Combination in Early SARS-CoV-2 Infection, medRxiv

A broadly neutralizing humanized ACE2-targeting antibody against SARS-CoV-2 variants

EGCG, a Green Tea Catechin, as a Potential Therapeutic Agent for Symptomatic and Asymptomatic SARS-CoV-2 Infection

A small molecule compound with an indole moiety inhibits the main protease of SARS-CoV-2 and blocks virus replication

Efficacy of GC-376 against SARS-CoV-2 virus infection in the K18 hACE2 transgenic mouse model

A Review on Remdesivir: A Possible Promising Agent for the Treatment of COVID-19

Remdesivir: Review of Pharmacology, Preclinical Data, and Emerging Clinical Experience for COVID-19

Mechanism of SARS-CoV-2 polymerase stalling by remdesivir

Remdesivir in The Treatment of COVID-19

Remdesivir for the Treatment of Covid-19 -Final Report

SARS-CoV-2 RNA dependent RNA polymerase (RdRp) targeting: an in silico perspective

Galidesivir, and Tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): A molecular docking study

Press Announcements

Characterization of the non-covalent interaction between the PF-07321332 inhibitor and the SARS-CoV-2 main protease

Pfizer's Novel COVID-19 Oral Antiviral Treatment Candidate Reduced Risk of Hospitalization or Death by 89% in Interim Analysis of Phase 2/3 EPIC-HR Study

Alam, Abida, Discovery, Development, and Patent Trends on Molnupiravir: A Prospective Oral Treatment for COVID-19

Abbreviated Profile of Drugs (APOD): modeling drug safety profiles to prioritize investigational COVID-19 treatments

Oseltamivir treatment prevents the increased influenza virus disease severity and lethality occurring in chronic ethanol consuming mice

Is oseltamivir suitable for fighting against COVID-19: In silico assessment, in vitro and retrospective study

Syncytia formation by SARS-CoV-2-infected cells

SARS-CoV-2 spike protein dictates syncytium-mediated lymphocyte elimination

Drugs that inhibit TMEM16 proteins block SARS-CoV-2 spike-induced syncytia

A randomised controlled trial of effectiveness and safety of Niclosamide as add on therapy to the standard of care measures in COVID-19 management

Immunophenotyping of COVID-19 and influenza highlights the role of type I interferons in development of severe COVID-19

Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome

Exacerbated innate host response to SARS-CoV in aged non-human primates

Influenza viruscytokine-protease cycle in the pathogenesis of vascular hyperpermeability in severe influenza

Cytokine Storm in COVID-19: The Current Evidence and Treatment Strategies

The deregulated immune reaction and cytokines release storm (CRS) in COVID-19 disease

The COVID-19 Cytokine Storm; What We Know So Far

Detectable Serum Severe Acute Respiratory Syndrome Coronavirus 2 Viral Load (RNAemia) Is Closely Correlated With Drastically Elevated Interleukin 6 Level in Critically Ill Patients With Coronavirus Disease

Tocilizumab: the first interleukin-6-receptor inhibitor

Effective treatment of severe COVID-19 patients with tocilizumab

Tocivid-19 investigators, Tocilizumab for patients with COVID-19 pneumonia. The single-arm TOCIVID-19 prospective trial

Clinical and Research Information on Drug-Induced Liver Injury, Bethesda (MD)

Anakinra for severe forms of COVID-19: a cohort study

The Effect of Anakinra in Hospitalized Patients with COVID-19: An Updated Systematic Review and Meta-Analysis

Effects of chloroquine on viral infections: an old drug against today's diseases?

COVID-19: Cytokine storm modulation/blockade with oral polyvalent immunoglobulins (PVIG, KMP01D): A potential and safe therapeutic agent (Primum nil nocere)

Impact of Hydroxychloroquine/Chloroquine in COVID-19 Therapy: Two Sides of the Coin

Hydroxychloroquine for Early Treatment of Adults With Mild Coronavirus Disease 2019: A Randomized, Controlled Trial

Pharmacology and Adverse Events of Emergency-Use Authorized Medication in Moderate to Severe COVID-19

Interleukin-6 receptor blockade in patients with COVID-19: placing clinical trials into context

A comprehensive review on sarilumab in COVID-19

Outcomes and biomarker analyses among patients with COVID-19 treated with interleukin 6 (IL-6) receptor antagonist sarilumab at a single institution in Italy

Canakinumab as treatment for COVID-19-related pneumonia: A prospective case-control study

Efficacy of canakinumab in mild or severe COVID-19 pneumonia

IL-18) as a target for immune intervention

Synergism of TNF-alpha and IFN-gamma Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes

Longitudinal Characterization of Cytokine Overproduction: A Case Report in Critically Ill COVID-19 Patients With Hyperinflammation in Bronchoalveolar Lavage

Cytokine storm intervention in the early stages of COVID-19 pneumonia

Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury

Evolution of JAK-STAT pathway components: mechanisms and role in immune system development

Object class segmentation of RGB-D video using recurrent convolutional neural networks

COVID-19: combining antiviral and anti-inflammatory treatments

Use of MRI for Personalized Treatment of More Aggressive Tumors

Beneficial impact of Baricitinib in COVID-19 moderate pneumonia; multicentre study

Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled trial

Baricitinib as potential treatment for 2019-nCoV acute respiratory disease

Members, Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19

The nuclear factor NF-kappaB pathway in inflammation

Targeting NF-kappaB pathway for the therapy of diseases: mechanism and clinical study

Intestinal Transcriptome Analysis Reveals Soy Derivative-Linked Changes in Atlantic Salmon

Inhibition of NF-kappaB-mediated inflammation in severe acute respiratory syndrome coronavirus-infected mice increases survival

Up-regulation of IL-6 and TNF-alpha induced by SARS-coronavirus spike protein in murine macrophages via NF-kappaB pathway

EGYVIR: An immunomodulatory herbal extract with potent antiviral activity against SARS-CoV-2

Discovery of novel pyrazole derivatives as a potent anti-inflammatory agent in RAW264.7 cells via inhibition of NF-kB for possible benefit against SARS-CoV-2

Repurposing of clinically approved drugs for treatment of coronavirus disease 2019 in a 2019-novel coronavirus-related coronavirus model

Cepharanthine Suppresses Herpes Simplex Virus Type 1 Replication Through the Downregulation of the PI3K/Akt and p38 MAPK Signaling Pathways

Small molecule screening identified cepharanthine as an inhibitor of porcine reproductive and respiratory syndrome virus infection in vitro by suppressing integrins/ILK/RACK1/PKCalpha/NF-kappaB signalling axis

Cepharanthine: An update of its mode of action, pharmacological properties and medical applications

Potential anti-COVID-19 agents

Cepharanthine: a review of the antiviral potential of a Japanese-approved alopecia drug in COVID-19

Pidotimod: a reappraisal

Modulation of airway epithelial cell functions by Pidotimod: NF-kB cytoplasmatic expression and its nuclear translocation are associated with an increased TLR-2 expression

Immunostimulants in respiratory diseases: focus on Pidotimod

Pidotimod: In-depth review of current evidence

Pidotimod in Paucisymptomatic SARS-CoV2 Infected Patients

Inflammation Triggered by SARS-CoV-2 and ACE2 Augment Drives Multiple Organ Failure of Severe COVID-19: Molecular Mechanisms and Implications

Saudi Critical Care Trial, Corticosteroid Therapy for Critically Ill Patients with Middle East Respiratory Syndrome

Long-term Systemic Corticosteroid Exposure: A Systematic Literature Review

Impact of corticosteroid therapy on outcomes of persons with SARS-CoV-2, SARS-CoV, or MERS-CoV infection: a systematic review and meta-analysis

The effect of corticosteroids on mortality of patients with influenza pneumonia: a systematic review and meta-analysis

Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis

Corticosteroids in septic shock: a systematic review and network meta-analysis

Dexamethasone in Hospitalized Patients with Covid-19

Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19: The CoDEX Randomized Clinical Trial

WHO welcomes preliminary results about dexamethasone use in treating critically ill COVID-19 patients

Dexamethasone, pro-resolving lipid mediators and resolution of inflammation in COVID-19

Baricitinib improves respiratory function in patients treated with corticosteroids for SARS-CoV-2 pneumonia: an observational cohort study

Convalescent plasma in Covid-19: Possible mechanisms of action

Bioactive natural compounds against human coronaviruses: a review and perspective

Traditional Chinese medicine as an adjunctive therapy for mild and common COVID-19: A systematic review and network meta-analysis

Reflections on treatment of COVID-19 with traditional Chinese medicine

Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 7)

Traditional Chinese Medicine (TCM) in the treatment of COVID-19 and other viral infections: Efficacies and mechanisms

Lianhuaqingwen exerts anti-viral and anti-inflammatory activity against novel coronavirus (SARS-CoV-2)

Effect of combination antiviral therapy on hematological profiles in 151 adults hospitalized with severe coronavirus disease

Total Face Approach (TFA): A Novel 3D Approach to Describe the Main Cephalometric Craniomaxillofacial Parameters

Effect of Jinhua Qinggan granules on novel coronavirus pneumonia in patients

Chinese Medicine Formula Huashibaidu Granule Early Treatment for Mild COVID-19 Patients: An Unblinded, Cluster-Randomized Clinical Trial

XueBiJing Injection Versus Placebo for Critically Ill Patients With Severe Community-Acquired Pneumonia: A Randomized Controlled Trial

Xuebijing Ameliorates Sepsis-Induced Lung Injury by Downregulating HMGB1 and RAGE Expressions in Mice

Efficacy and safety of Xuebijing injection (a Chinese patent) for sepsis: A meta-analysis of randomized controlled trials

Emerging SARS-CoV-2 Variants: A Review of Its Mutations, Its Implications and Vaccine Efficacy

Impact of the Delta variant on vaccine efficacy and response strategies

Science Brief: Omicron (B.1.1.529) Variant, CDC COVID-19 Science Briefs

OMICRON (B.1.1.529): A new SARS-CoV-2 variant of concern mounting worldwide fear

Omicron Variant (B.1.1.529): Infectivity, Vaccine Breakthrough, and Antibody Resistance

Postinfection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection

Increased resistance of SARS-CoV-2 variant P.1 to antibody neutralization

SARS-CoV-2 B.1.1.7 sensitivity to mRNA vaccine-elicited, convalescent and monoclonal antibodies, medRxiv

Potent neutralizing nanobodies resist convergent circulating variants of SARS-CoV-2 by targeting diverse and conserved epitopes

N-terminal domain antigenic mapping reveals a site of vulnerability for SARS

Correlates of SARS-CoV-2 Variants on Deaths, Case Incidence and Case Fatality Ratio among the Continents for the Period of

Insights into SARS-CoV-2's Mutations for Evading Human Antibodies: Sacrifice and Survival

Transmission, infectivity, and neutralization of a spike L452R SARS-CoV-2 variant

SARS-CoV-2 variants, spike mutations and immune escape

Complete map of SARS-CoV-2 RBD mutations that escape the monoclonal antibody LY-CoV555 and its cocktail with LY-CoV016

Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization

Delta spike P681R mutation enhances SARS-CoV-2 fitness over Alpha variant, bioRxiv

Druggable targets of SARS-CoV-2 and treatment opportunities for COVID-19

The mechanism of resistance to favipiravir in influenza

Emerging SARS-CoV-2 mutation hot spots include a novel RNA-dependent-RNA polymerase variant

RdRp mutations are associated with SARS-CoV-2 genome evolution

SARS-CoV-2 genetic variations associated with COVID-19 pathogenicity

Mutational spectra of SARS-CoV-2 orf1ab polyprotein and signature mutations in the United States of America

Novel mutations in NSP-1 and PLPro of SARS-CoV-2 NIB-1 genome mount for effective therapeutics

Effective drugs used to combat SARS-CoV-2 infection and the current status of vaccines

Antibody Resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7

SARS-CoV-2 mutations: the biological trackway towards viral fitness

Identification of SARS-CoV-2-induced pathways reveals drug repurposing strategies

Traditional Chinese Medicine in the Treatment of Patients Infected with 2019-New Coronavirus (SARS-CoV-2): A Review and Perspective

Incorporation fidelity of the viral RNA-dependent RNA polymerase: a kinetic, thermodynamic and structural perspective

Immune suppression in the early stage of COVID-19 disease

Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury

Characteristics of patients with coronavirus disease (COVID-19) confirmed using an IgM-IgG antibody test

Role of monoclonal antibody drugs in the treatment of COVID-19

Mechanical Ventilation: State of the Art

N764K; D796Y; Q954H; N969K

DEL69/70; T95I; G142D

DEL143/145; N211I

DEL212/212; G339D

DEL247/253; L452Q

The mutations of amino acid in SARS-CoV-2 S protein are presented. The summarized information represented in the table was derived from the public data

Formal analysis: Zhihui Ruan, Yicong Liang

Writing -original draft: Jialing Yin, Chengcheng Li

All authors had finally approved the version of the manuscript to be published and agreed to be accountable for all aspects of the work

All authors had finally approved the version of the manuscript to be published and agreed to be accountable for all aspects of the work.

We declare no competing interests.

 Tables   Table 1 Summary of approved and developed drugs against COVID-