key: cord-0766707-b69zgnku
authors: Huang, Boxuan; Ling, Rongsong; Cheng, Yifan; Wen, Jieqi; Dai, Yarong; Huang, Wenjie; Zhang, Siyan; Lu, Xifeng; Luo, Yifeng; Jiang, Yi-Zhou
title: Characteristics and Therapeutic Options of the Coronavirus Disease 2019
date: 2020-06-24
journal: Mol Ther Methods Clin Dev
DOI: 10.1016/j.omtm.2020.06.013
sha: 5fabf177fcbd3f34cdb69367648bf12c4778e37c
doc_id: 766707
cord_uid: b69zgnku

Abstract The Coronavirus Disease 2019 (COVID-19) is a new type of pneumonia caused by SARS-CoV-2 infection. COVID-19 is affecting millions of patients and the infected number keeps increasing. SARS-CoV-2 is highly infectious, has a long incubation period, and causes a relatively high death rate, resulting in severe health problem all over the world. Currently there is no effective proven drugs for the treatment of COVID-19, therefore, development of effective therapeutic drugs to suppress SARS-CoV-2 infection is urgently needed. In this review, we first summarize the structure and genome features of SARS-CoV-2, and introduce its infection and replication process. Then we review the clinical symptoms, diagnosis and treatment options of COVID-19 patients. We further discuss the potential molecular targets and drug development strategies for treatment of the emerging COVID-19. Finally, we summarize clinical trials of some potential therapeutic drugs and the results of vaccine development. This review provides some insights for the treatment of COVID-19.

The Coronavirus Disease 2019 caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is now affecting millions of patients all over the world by May 30, 2020. 1, 2 And according to WHO statistics on March 3, the mortality rate among confirmed COVID-19 cases was 3.4%. As of May 22, according to Worldometer, the mortality rate is nearly 5.9%. While in Italy, the mortality rate is over 13%. The SARS-CoV-2 coronavirus is a type of single-stranded RNA virus that belongs to the Coronaviruses family. [1] [2] [3] Coronaviruses can be divided into four groups:

Alphacoronavirus (αCoV), Betacoronavirus (βCoV), Gammacoronavirus(γCoV) and

Deltacoronavirus(δCoV). 1 Currently, seven coronaviruses are known to infect human, including two alpha-coronaviruses (HCoV-229E and HKU-NL63) and five beta-coronaviruses (HCoV-OC43, HCoV-HKU1, SARS-CoV, MERS-CoV, and SARS-CoV-2). In the past two decades, three previously unknown beta-coronaviruses, SARS-CoV, MERS-CoV, and SARS-CoV-2, have emerged. 2 These deadly coronaviruses cause lower respiratory tract infections, resulting in acute pneumonia, respiratory distress, cytokine storms, multiple organ dysfunctions, and even patient death. [1] [2] [3] In this review, we highlight the pandemic of the emerging COVID-19, review the key molecular and clinical characteristics of SARS-CoV-2, and discuss the potential options for developing drugs for the treatment of COVID-19.

The genome of SARS-CoV-2 contains 29903 nucleotides (NC_045512.2), of which the GC content is 38%. The SARS-CoV-2 genome encodes about 9860 amino acids. Similar to other coronaviruses, the SARS-CoV-2 genome consists of two flanked non-translation regions (UTRs), a 5' long open reading frame (ORF1a/b) that encode polyproteins, and several structural protein encoding ORFs ( Figure 1 ). [1] [2] [3] The polyprotein encoded by 5'ORF1a / b is cleaved by Papain-like cysteine protease (PLpro) and 3C-like serine protease (3Clpro or M pro ). This process produces 16 non-structural proteins (nsps), including nsp3 , nsp5, nsp12 (RNA-dependent RNA polymerase (RdRp), nsp13 (Helicase) and other nsps that may be involved in viral transcription and replication. 1, 2 And the 3' ORFs encode structural proteins spike (S), envelope I, membrane (M) and nucleocapsid (N). It had been reported that the ORFs of SARS-CoV-2 shares high similarity with SARS-CoV. 1,2 And the main differential regions between SARS-CoV-2 and SARS-CoV genomes are located in the ORF3b, spike protein (S) and ORF8. Of which the spike protein (S) and ORF8 region was previously reported to be recombination hotspot regions. 1, 2, 13 The transmission and infection process of SARS-CoV-2 Similar to SARS-CoV, SARS-CoV-2 also uses Angiotensin converting enzyme II (ACE2) as a cellular entry receptor, suggesting that the infection process of SARS-CoV-2 into cells could be similar to that of SARS-CoV. 9, 14, 15 Coronavirus enters into the host cells through the endosomal or lysosomal pathway in a proteolysis-dependent manner. 16 The S protein of the coronavirus interacts with ACE2 protein on the host cells. Then the S protein is cleaved into S1 and S2 subunits. The fusion peptide (FP) domain of S2 subunits is embedded in the host cell membrane, and the transmembrane domain (TM) of the S2 protein sub-type is embedded into the virus. After that a hexapolymer hairpin structure is formed with the FP-HR1 domain and the TM-HR2 domains, which brings the spatial distance between the host cell and the virus, and facilitates the membrane fusion and virus entry. 17 A recent study compared the affinity between SARS-CoV-2 and SARS-CoV S proteins to the receptor ACE2 and revealed that the affinity between SARS-CoV-2 to ACE2 is 10 to 20 times higher than that of SARS-CoV. 17 This might explain the higher infectious capacity and wide-spread outcome of SARS-CoV-2.

The known transmission pathways of SARS-CoV-2 in the human include: 1).

Inhaling tiny droplets carrying virus; 2). Close contact with virus carriers; 3).Contact with a surface contaminated by SARS-CoV-2; 4). Aerosol transmission. 18 And the latest research showed that in animals that are close contact with humans, SARS-CoV-2 can efficiently replicate in cats, and the virus transmits in cats via respiratory droplets. 19, 20 Serological studies revealed that cats owned by COVID-19 patients had the highest neutralization titer for SARS-CoV-2. These studies pointed out the risk of cats involved in the transmission of SARS-CoV-2. [19] [20] [21] So, it is important that people and pets keep an appropriate distance.

Considering the genomic structure and other characteristics of SARS-CoV-2, its replication and amplification processes should be similar to other coronaviruses such as SARS-CoV. 11, 22, 23 After the membrane fusion, the viral RNA genome is released into the cytoplasm of the host cells. Then the ORF1a/b is translated into polyprotein 1a/1ab (pp1a/pp1ab), which are cleaved into 16 nsps. 11, 22, 23 

The diagnosis of SARS-CoV-2 infection was based on nucleic acid detection. [24] [25] [26] The mouth/nasopharyngeal swab samples or bronchoalveolar lavage fluid (BALF) samples were collected from the suspected patients and used for detection of SARS-CoV-2 with Reverse Transcription-Polymerase Chain Reaction (RT-PCR). The nucleic acid detection is a multi-step method that involves RNA isolation, reverse transcription and PCR with virus-specific primers. RNA could be degraded during clinical sample transfer and RNA isolation process, leading to false negative results.

Also, in certain early stage patients, the virus titer in the mouth/ nasopharyngeal swab samples could be too low to be detected, which further increases the false negative rates. According to a report, the positive rate of detection of COVID-19 using fluorescent quantitative RT-PCR as the detection method is only 30-50%, which means it has a high false negative rate. And studies have shown that thermal inactivation adversely affects the SARS-CoV-2 detection efficiency of RT-PCR, which is an important reason for the false negative rate. 27 In addition, the IgG/IgM antibody detection is also important for the diagnosis of SARS-CoV-2 infection.

Depending on a report based on the antibody responses of 285 COVID-19 patients, approximately 17-19 days after the onset of symptoms, 100% of patients developed virus-specific IgG, while the proportion of patients with virus-specific IgM peaked at 94.1% after 20-22 days. And titers of IgG/IgM antibodies tended to be stable within 6 days after seroconversion, which means that serological testing may be helpful for the diagnosis of suspected patients whose RT-PCR results are negative. 28 Recently, computerized tomography scan (CT) was proposed to assist in the diagnosis of SARS-CoV-2 infection. 25, [29] [30] [31] CT scan revealed that SARS-CoV-2 infection causes bilateral pulmonary parenchymal ground-glass and consolidative pulmonary opacities in the lung. In addition, other features including absence of lung cavitation, discrete pulmonary nodules, pleural effusions, and lymphadenopathy could be discovered with CT scanning. Therefore, CT scan provides a quick overview of the status and severity of the disease. 25, [31] [32] [33] [34] [35] [36] [37] 13 However, CT images of SARS-CoV-2 infected lungs partially overlap with the images of other lung infectious diseases. And during the early stage of infection, the patients might not have significant lung image changes. Therefore, the combination of nucleic acid detection and CT scan is recommended for the precise detection of SARS-CoV-2 infection. [25] [26] [29] [30] [31] The incubation period of SARS-CoV-2 ranges from 1 to 14 days (interquartile range, 2 to 7 days). 1, 7, [38] [39] [40] Clinical symptoms of SARS-CoV-2 infection include fever, dry cough, fatigue. More than 90% of the patients had fever, about 50-76% patients had cough and around 25.3%-44% of the patients had fatigue symptoms. 1, 2 Other not common symptoms include sputum production, rhinorrhea, sore throat, chest tightness, headache, vomiting and diarrhea. Some patients only showed mild fatigue, low fever, no pneumonia, or even no symptoms. Clinically, based on the disease severity, patients can be divided into light, common, moderate and critical condition groups. 1, 7, 13, 41 Most critical condition patients had breathing difficulties and/or hypoxemia. And the high incidence of multiple organ dysfunctions is one of the characteristics of COVID-19. 42 In some severe cases, it can quickly progress into sepsis shock, acute respiratory distress syndrome, blood clotting dysfunction and metabolic acidosis. In patients with coagulopathy, serological tests showed the existence of anticardiolipin IgA antibodies and anti-β 2 -glycoprotein IgA and IgG antibodies. 43 However, the exact mechanisms that cause these symptoms remain to be explored, the organ dysfunctions maybe one of the causes of these symptoms.

According to a research in New York City, most of critically ill COVID-19 patients are associated with comorbidities, including hypertension, diabetes, chronic cardiovascular disease and kidney disease. And the mortality rates of patients with these comorbidities are relatively high. 44 The severity of SARS-CoV-2 infected patients is also associated with age, and the number of deaths is concentrated in people over 40 years of age or older. Studies revealed that morbidity of children and infants are fewer than adults. 45, 46 This may be due to differences in the affinity between the receptor and the virus in different populations. [46] [47] [48] [49] 

Currently there is no specific drug available to block SARS-CoV-2 infection or RdRp has revealed more potent drug since they tightly bind to the RdRp of SARS-CoV-2. In addition, they found that guanosine derivative (IDX-184), Setrobuvir and YAK can be the top seeds for antiviral treatments. 63 Moreover, through a large-scale computer-assisted drug screening, China's joint scientific research team found that both Saquinavir and Ritonavir can inhibit the activity of SARS-CoV-2 M pro and can also act as the NSP 16 inhibitor; 64 2). The spike protein S: The S protein facilitates the membrane fusion and virus entry by interacting with the interacts with ACE2 protein on the host cells. 14, 17 It's reported that the affinity between SARS-CoV-2 to ACE2 is 10 to 20 times higher than that of SARS-CoV, suggesting that the blocking S protein mediated virus infection could be an effective strategy for COVID-19 treatment. 14, 17 Blocking peptides or monoclonal antibodies against S proteins are currently under investigation for their function in inhibiting SARS-CoV-2 infection. 65 In addition, targeting the proteases including PLpro or 3CLpro could result in the decreased expression of NSPs, therefore inhibiting the replication and infection of SARS-CoV-2 ( Figure 3) . 58, 60 Potential molecular targets of SARS-CoV-2 could provide strategies for drug screening and development. There are currently three main strategies to target SARS-CoV-2. Considering the urgent need of therapeutic drugs, the first and best strategy is to the test existing broad-spectrum antiviral drugs to assess the effects of these drugs on SARS-CoV-2. 6,57, 66 The advantage of testing the broad-spectrum antiviral drugs is that the safety of those drugs has been proven, therefore if an antiviral drug can inhibit the replication or infection of SARS-CoV-2, it could be quickly applied for the clinical therapy of COVID-19. 67 For example, the antimalarial drug chloroquine has broad-spectrum antiviral activity, although it cannot be regarded as a special effect, but can be used as an effective drug. [67] [68] [69] [70] [71] [72] [73] [74] At the same time, in Traditional Chinese Medicine and natural products, there are some prescriptions that have broad spectrum inhibition effect for viruses, such as the Lianhua Qingwen

Capsule. [53] [54] [55] The second method is to screen the existing bioactive compounds that to identify small molecule inhibitors or natural compounds for SARS-CoV-2. 6, 57, 66 High-throughput screening of many easily available compounds is performed to screen for compounds that inhibit SARS-CoV-2 replication or infection. The main drawback of this approach is that while many of the identified drugs are active in vitro against coronaviruses, most are not suitable for clinical use. One reason is that they could be associated with immunosuppression, and another important reason is that their semi-maximum effective concentration (EC50) value may significantly exceed the peak serum concentration (Cmax) level at the therapeutic dose. 6 anti-coronavirus activity, with limited side effects. Antisense oligonucleotides, monoclonal antibodies and antiviral peptides are biologically targeted drugs, and their pharmacodynamics, pharmacodynamics and side effects are easy to be characterized. 65, 75, 76 In addition, these bio-targeted drugs have a short development cycle and can be used quickly in clinical settings.

In general, during the COVID-19 pandemic, the above methods can be used in combination to determine the best treatment options in time. And, in the fight against the outbreak in China, the existing chemical/Chinese medicine and the bio-targeted drug are more used during outbreaks due to the short development cycle and the current urgent need of therapeutic drugs.

As discussed above, the existing broad-spectrum antiviral drugs could be the ideal therapeutic drugs the COVID-19 treatment. Here we review the some of the potential therapeutic drugs that are under clinical trials to test their capacities to inhibit SARS-CoV-2 replication or infection. Remdesivir is a nucleotide analog with broad-spectrum antiviral activity, which is formally known as GS-5734. It's a RdRp inhibitor that was initially developed for treatment of Ebola virus infected patients.

cells, 77 therefore currently multiple clinical trials are ongoing to test its function for the COVID-19 treatment. According to a recent report, which is based on data from severe COVID-19 patients treated with compassionate-use Remdesivir from January 25 to March 7, 2020, clinical improvement was observed in 36 of 53 patients (68%), one of its criteria is the oxygen-support class. 78 Other RdRp inhibitors including Favipiravir, Ribavirin and Penciclovir could also be used as candidate therapeutic drugs due to their function in inhibiting the replication of coronaviruses. 77 Hydroxychloroquine and Chloroquine, the immunosuppressive drugs previously approved for malaria treatment, have anti-inflammatory effects by impairing antigen presentation via the lysosomal pathway. 79 (Table 1) . 89 Moreover, there has been evidence that people with underlying diseases such as hypertension and other cardiovascular diseases have a higher critical rate after being infected with SARS-CoV-2. 90 

patients. It was shown that patients using angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs), had a lower rate of severe cases. The level of IL-6 in peripheral blood and peak viral load are decreased, CD3 and CD8 T cell counts are increased, compared to other antihypertensive therapy.

This evidence may contribute to reduce the mortality rate of patients with hypertension after infected with SARS-CoV-2. 91

Multiple clinical trials have been launched on potential therapeutic drugs that may be effective with COVID-19. As for Remdesivir, the most recent report has indicated its clinical improvement for severe COVID-19. 78 Although previous clinical trial showed no difference in clinical improvement time between the treatment with Lopinavir/Ritonavir and standard care, [84] [85] Lopinavir/Ritonavir is relatively safe and can significantly decrease SARS-CoV-2 viral loads in certain patients, 83 so several clinical trials were conducted. In a randomized open-label phase 2 trial with a triple combination of interferon beta-1b, Lopinavir-Ritonavir and Ribavirin, when gave treatment within 7 days of symptom onset, is significant in reducing the shedding of SARS-CoV-2, compared with using Lopinavir-Ritonavir alone. 93 As for Chloroquine, a multinational registry analysis revealed that the use of Hydroxychloroquine or Chloroquine (with or without combination treatment of macrolide) was not beneficial to the treatment of patients infected with COVID-19, on the contrary, it increased the risk of ventricular arrhythmias and in-hospital death. 94 Based on this, WHO halted trials of hydroxychloroquine over safety fears. Whilea multicenter prospective observational study showed that the proportion of patients receiving chloroquine for 10 and 14 days without detectable viral RNA was significantly higher than the non-chloroquine group (91.4% and 95.9% respectively VS 57.4% and 79.6% respectively). And most of these patients were moderate, which revealed the therapeutic potential of chloroquine for early stage patients. 95 These findings indicate that before the widespread adoption of some drugs, the results of ongoing prospective, randomized, controlled studies are very important. In addition, the result of another prospective multicenter open-label randomized controlled trial on Lianhua Qingwen capsule revealed that Lianhua Qingwen capsule could be considered to ameliorate clinical symptoms of COVID-19. 96 Although more than 300 clinical trials for COVID-19 are underway, there is no clinical data supporting any prophylactic therapy, and there is no randomized clinical trials data that any potential therapy can improve outcomes in COVID-19 patients yet. 13, 97 With the worldwide pandemic of COVID-19, the development for vaccines against COVID-19 becomes more urgent. On March 16, 2020, the first COVID-19 vaccine candidate entered human clinical trials. As of May 20 2020, more than 120 candidate vaccines are under development (WHO data). For most of these candidates, the method is to block the S protein of SARS-CoV-2 by inducing neutralizing antibodies and prevent it from binding to the ACE2 receptor. There is an indication that vaccines could be available by early 2021. 98 vaccine. This is a vaccine that expresses the S protein of SARS-CoV-2 through a recombinant adenovirus type 5 (Ad5) vector. It was safe and tolerated in a total of 108 healthy adults in three groups, and could induce an immune response against SARS-CoV-2 in human body. The final results will be assessed within six months. 99 And the vaccine is currently undergoing phase 2 clinical trial. According to a report from SINOPHARM, the inactivated anti-SARS-CoV-2 vaccine developed by SINOPHARM has been approved for phase 1 and phase 2 clinical trials by the NMPA.

In the process of vaccine development, there are some difficulties should be considered, such as the lack of animal models for in vivo drug efficacy evaluation, and the higher mutation rate of coronavirus, as well as the possible antibody-dependent enhancement (ADE) effect in SARS-CoV-2.

The pandemic of COVID-19 has caused severe health problem all over the world. In order to curb the growth rate of SARS-CoV-2 infected patients, superspreading events is non-negligible, according to a news report on the Science, perhaps 10% of the infected people caused 80% of the spread. 100 And it is important to avoid superspreading events by restricting gathering. In addition, strategies including quarantine and personal protective equipment are essential for to stop further spread of COVID-19. The rapid development of therapeutic drugs targeting SARS-CoV-2 is urgently needed for the treatment of current COVID-19 patients. For example, based on the highly conserved substrate-binding pocket among coronavirus M pro (or 3CLpro), the combination of structure-based drug design, virtual screening and high-throughput screening could help us find more effective anti-SARS-CoV-2 drug leads or treatment strategies. 101 In the long term, it is more important to develop vaccines against COVID-19 and provide active acquired immunity to COVID-19. Conceptualization, Funding acquisition, Writing-review&editing.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (5) With the global pandemic of COVID-19, the development of effective therapeutic drugs and options has become more urgent. In this review, Boxuan Huang et al. mainly focuses on the characteristics of COVID-19, the key molecular targets of SARS-CoV-2, relative drug clinical trial results, and progress in vaccine development.

Review of the Clinical Characteristics of Coronavirus Disease 2019 (COVID-19)

Evolutionary Trajectory for the Emergence of Novel Coronavirus SARS-CoV-2. Pathogens

Novel 2019 coronavirus SARS-CoV-2 (COVID-19): An updated overview for emergency clinicians

Genome Composition and Divergence of the Novel Coronavirus (2019-nCoV) Originating in China

Coronavirus diversity, phylogeny and interspecies jumping

Coronaviruses -drug discovery and therapeutic options

Clinical Characteristics of Coronavirus Disease 2019 in China

Severe acute respiratory syndrome coronavirus as an agent of emerging and reemerging infection

A pneumonia outbreak associated with a new coronavirus of probable bat origin

Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding

Emerging coronaviruses: Genome structure, replication, and pathogenesis

Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission

A Review of SARS-CoV-2 and the Ongoing Clinical Trials

Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation

Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine

Coronavirus cell entry occurs through the endo-/lysosomal pathway in a proteolysis-dependent manner

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

Aerodynamic analysis of SARS-CoV-2 in two Wuhan hospitals

Susceptibility of ferrets, cats, dogs, and other domesticated animals to SARS-coronavirus 2

SARS-CoV-2 neutralizing serum antibodies in cats: a serological investigation

Spike protein recognition of mammalian ACE2 predicts the host range and an optimized ACE2 for SARS-CoV-2 infection

Coronaviruses: an overview of their replication and pathogenesis

Coronaviruses post-SARS: update on replication and pathogenesis

Differential diagnosis of illness in patients under investigation for the novel coronavirus (SARS-CoV-2)

Diagnosis of SARS-CoV-2 Infection based on CT scan vs. RT-PCR: Reflecting on Experience from MERS-CoV

The SARS-CoV-2 Outbreak: Diagnosis, Infection Prevention, and Public Perception

Potential False-Negative Nucleic Acid Testing Results for Severe Acute Respiratory Syndrome Coronavirus 2 from Thermal Inactivation of Samples with Low Viral Loads

Antibody responses to SARS-CoV-2 in patients with COVID-19

Combination of RT-qPCR testing and clinical features for diagnosis of COVID-19 facilitates management of SARS-CoV-2 outbreak

Diagnosis and clinical management of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) infection: an operational recommendation of Peking Union Medical College Hospital (V2.0)

CT screening for early diagnosis of SARS-CoV-2 infection

Clinical and CT imaging features of 2019 novel coronavirus disease (COVID-19)

CT Imaging Features of 2019 Novel Coronavirus

Clinical and CT imaging features of 2019 novel coronavirus disease (COVID-19)

CT chest findings in coronavirus disease-19 (COVID-19)

Coronavirus Disease 2019 (COVID-19): Role of Chest CT in Diagnosis and Management

Sensitivity of Chest CT for COVID-19: Comparison to RT-PCR

Clinical features and obstetric and neonatal outcomes of pregnant patients with COVID-19 in Wuhan, China: a retrospective, single-centre, descriptive study

Clinical progression of patients with COVID-19 in Shanghai

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Clinical course and mortality risk of severe COVID-19

Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study

Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19

Critically ill patients with COVID-19 in

COVID-19 in Children: Initial Characterization of the Pediatric Disease

Sah, R. 2019 Novel Coronavirus Disease

COVID-19 Therapeutic and Prevention

Remdesivir as a possible therapeutic option for the COVID-19

Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors

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

Perspectives on monoclonal antibody therapy as potential therapeutic intervention for Coronavirus disease-19 (COVID-19)

Therapeutic options for the treatment of 2019-novel coronavirus: An evidence-based approach

A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19

The Trial of Chloroquine in the Treatment of Corona Virus Disease 2019 (COVID-19) and Its Research Progress in Forensic Toxicology

Could chloroquine /hydroxychloroquine be harmful in Coronavirus Disease 2019 (COVID-19) treatment?

Insights from nanomedicine into chloroquine efficacy against COVID-19

Aminoquinolines against coronavirus disease 2019 (COVID-19): chloroquine or hydroxychloroquine

New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19?

Of chloroquine and COVID-19

Chloroquine and hydroxychloroquine as available weapons to fight COVID-19

Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery

Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

Compassionate Use of Remdesivir for Patients with Severe Covid-19

Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology

Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro

In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

Case of the Index Patient Who Caused Tertiary Transmission of COVID-19 Infection in Korea: the Application of Lopinavir/Ritonavir for the Treatment of COVID-19 Infected Pneumonia Monitored by Quantitative RT-PCR

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19

The First Case of 2019 Novel Coronavirus Pneumonia Imported into Korea from Wuhan, China: Implication for Infection Prevention and Control Measures

Arbidol as a broad-spectrum antiviral: an update

Arbidol: a broad-spectrum antiviral compound that blocks viral fusion

Mechanism of inhibition of enveloped virus membrane fusion by the antiviral drug arbidol

Arbidol combined with LPV/r versus LPV/r alone against Corona Virus Disease 2019: A retrospective cohort study

Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention

Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension

Remdesivir for the Treatment of Covid-19 -Preliminary Report

Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial

Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis

Preliminary evidence from a multicenter prospective observational study of the safety and efficacy of chloroquine for the treatment of COVID-19

Efficacy and Safety of Lianhuaqingwen Capsules, a repurposed Chinese Herb

Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review

The COVID-19 vaccine development landscape

Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial

Why do some COVID-19 patients infect many others, whereas most don't spread the virus at all?

Structure of M(pro) from SARS-CoV-2 and discovery of its inhibitors