key: cord-0904152-b8g5puet
authors: Basu, Debdoot; Chavda, Vivek P.; Mehta, Anita A.
title: Therapeutics for COVID-19 and post COVID-19 complications: An update
date: 2022-02-04
journal: Curr Res Pharmacol Drug Discov
DOI: 10.1016/j.crphar.2022.100086
sha: a03e67373687296556ea1fd3817344960b0f5a90
doc_id: 904152
cord_uid: b8g5puet

Since its inception in late December 2020 in China, novel coronavirus has affected the global socio-economic aspect. Currently, the world is seeking safe and effective treatment measures against COVID-19 to eradicate it. Many established drug molecules are tested against SARS-CoV-2 as a part of drug repurposing where some are proved effective for symptomatic relief while some are ineffective. Drug repurposing is a practical strategy for rapidly developing antiviral agents. Drug repurposing typically begins with virtual screening of existing drugs using docking experiments. Many drugs are presently being repurposed utilizing basic understanding of disease pathogenesis and drug pharmacodynamics, as well as computational methods. In the present situation, drug repositioning could be viewed as a new treatment option for COVID-19. Several new drug molecules and biologics are engineered against SARS-CoV-2 and are under different stages of clinical development. A few biologics drug products are approved by USFDA for emergency use in the covid management. Due to continuous mutation, many of the approved vaccines are not much efficacious to render the individual immune against opportunistic infection of SARS-CoV-2. Hence, there is a strong need for the cogent therapeutic agent for covid management. In this review, a consolidated summary of the therapeutic development against SARS-CoV-2 is depicted along with an overview of effective management of post COVID-19 complications.

Coronavirus disease 2019 , which has begun in Wuhan city of China, and has already marked its presence globally with reports of reinfections due to endemics caused by the viral mutations (Indari et al., 2021; Tillett et al., 2021) . Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19 (Chavda et al., 2021e; Indari et al., 2021) . The cell receptor neuropilin-1 was discovered to be involved in SARS-CoV-2 entrance (Indari et al., 2021) . Based on clinical symptoms, COVID-19 is classified as mild, moderate, or severe (Smail et al., 2021) .

Angiotensin-converting enzyme 2 (ACE-2) is the fusion receptor responsible for the attachment of the SARS-CoV-2 with host (Chavda et al., 2021; Zhou et al., 2020) ACE-2 receptor is found in the lungs, heart, kidney, intestine, and endothelium, indicating that viruses can attach to a wide range of organs (Chavda et al., 2021f; Hadizadeh, 2021) . Increased levels of proinflammatory cytokines like interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), IL-1, interferon-γ-inducible protein (IP10) and chemokines, while decreased levels of cytotoxic T-lymphocytes (CTLs), helper (Th) cells, interferon γ (IFNγ) expressing (Th) cells characterize SARS-CoV-2 that corresponds to cytokine storm (Chavda et al., 2021b; Smail et al., 2021) This condition of hyperinflammation causes oxidative stress, which damages endothelial and alveolar cells in the lungs. Damage to these cells compromises the pulmonary membrane, resulting in vascular leakage, increased lung edema, and acute respiratory distress syndrome (ARDS) (Smail et al., 2021) . Chemokines attract macrophages and neutrophils to the lungs, resulting in acute lung injury (ALI), disseminated intravascular coagulation, multiple organ dysfunction, and death in patients with severe COVID-19 (Smail et al., 2021) .

Viruses constantly change through mutation (CDC, 2021; Chavda et al., 2021a) . Many variants of SARS-CoV-2 have been detected all around the world during this epidemic (Chavda et al., 2021a) .

The countries with the most cases were United States of America (48413265 cases) India (34,615,757 cases) , Brazil (22, 105, 872 cases) , United Kingdom (10,329,078 cases) and Russian Federation (9,737,037 cases) (World Health Organization, 2021) It is estimated that around 70% of the world's population will need to gain immunity against SARS-CoV-2 to acquire herd immunity (Dhar Chowdhury and Oommen, 2020) . For achieving herd immunity against COVID-19, researchers around the world constantly developing vaccines.

Most people who got fully vaccinated with both doses were United Arab Emirates (90.3%) followed by Singapore (87.88%), Portugal (86.2%), Malta (86%) (Ourworldindata.org, 2020) . In WHO, research is going on for finding candidates for developing better vaccines against COVID-19 (Dhar Chowdhury and Oommen, 2020).

The process of identifying new targets for existing medications is known as drug repurposing, and it is regarded as a cost-effective and efficient method (Jang et al., 2021; Singh et al., 2020) .It is estimated that 75% of already available drugs may be repurposed to treat a variety of diseases . Outbreaks of SARS-CoV-2, present particular obstacles to clinicians in terms of selecting suitable pharmacological drugs in a clinical setting with little time for novel drug discovery (Bakowski et al., 2021) . Repurposing existing medicines for the treatment of multiple diseases has recently become a common technique since it utilizes risk-free compounds with familiar pharmacodynamic, preclinical, and pharmacokinetic profiles that can go straight through the late phase of clinical trials, allowing the development of drug process effectively low-price and faster (Wang and Guan, 2021) . Therefore, the quest for successful COVID-19 therapeutic drugs are critical and immediate (Fig. 4 ).

J o u r n a l P r e -p r o o f

Remdesivir has a wide range of antiviral activities against coronaviruses Smith et al., 2020) . Previously, remdesivir was used as an investigational drug for the ebola virus .The possible mechanism of action by which remdesivir may help to treat COVID-19

is by inhibition of viral replication. The enzyme RNA-dependent RNA polymerases (RdRps) are needed for SARS-CoV-2 replication. Remdesivir is a mono-phosphoramidite prodrug of remdesivir-triphosphate (RDV-TP), an adenosine analog that inhibits RdRps Smith et al., 2020) . Adenosine-triphosphate competes with remdesivir-TP for insertion into embryonic viral RNA chains. Since RDV-TP does not induce immediate chain termination, it terminates RNA synthesis until it is integrated into viral RNA Smith et al., 2020) . Several clinical trials are going on all over the world for its efficacy against COVID-19 (Table 1) . A clinical study in the US reported that remdesivir improved clinical conditions of severe COVID-19 patients (Hoek et al., 2021; . When patients with severe COVID-19 were given remdesivir, symptomatic improvement was seen in a clinical study (Ader et al., 2021; Buckland et al., 2020) . Currently, remdesivir is the only USFDA approved repurposed drug for severe COVID-19 conditions (Authorization, 2021) .

Favipiravir is approved in Japan for influenza viruses . Favipiravir is a prodrug of purine nucleotide which converts into active form favipiravir-ribofuranosyl triphosphate (favipiravir-RTP) within the tissue, works by inhibiting the SARS-CoV-2's RdRp enzyme. It allows favipiravir to be easily inserted into viral RNA thus sparing human DNA which results in J o u r n a l P r e -p r o o f

Molnupiravir, the prodrug of ribonucleoside analog of β-D-N4-hydroxycytidine (Vicenti et al., 2021) . It has been shown to prevent the replication of a variety of viruses with low cytotoxicity and a high degree of resistance. When the active form of a drug gets incorporated in the virus instead of uracil or cytosine during RNA synthesis which causes G to A and C to U transformations in a dose-dependent manner resulting in deadly mutagenesis through the entire genome of many viruses (Fischer et al., 2021; Vicenti et al., 2021) . This possible mechanism of action of molnupiravir may also prevent viral replication viainhibitingSARS-CoV-2-RdRp in a host cell (Vicenti et al., 2021) . The efficacy of molnupiravir was proved against influenza and various coronaviruses (Kabinger et al., 2021) . A clinical study is going for the efficacy of molnupiravir against COVID-19 (Table 1) .

J o u r n a l P r e -p r o o f AT-527 is a double prodrug of a guanosine nucleotide analog that has shown effective in vitro and in vivo activity against hepatitis C virus (HCV)by specifically inhibiting RdRp (Good et al., 2021) .

Good et al found that in an in vitro study, where AT-527 shows potent activity for COVID-19.

Clinical trials are underway regarding the efficacy of AT-527 (Table 1) .

Ivermectin is a macrocyclic lactone with a wide-range of anthelmintic actions (Rizzo, 2020) . It is a nuclear transport inhibitor facilitated by the importin αβ/1 heterodimer, which is responsible for the translocation of viral proteins needed for the replication of RNA viruses (Rizzo, 2020) . It also shields S protein which binds to transmembrane receptor CD147 and ACE-2 (Kaur et al., 2021) .

Ivermectin's antiviral effect may also be due to allosteric regulation of the P2X4 receptor, which are cation-selective channels that are gated by extracellular ATP and serve as an ionophore (Kaur et al., 2021) . Anti-inflammatory activity of ivermectin is also proved in mice study which may mitigate cytokine storm in COVID-19 (Kaur et al., 2021) . Caly et al. reported that ivermectin inhibits SARS-CoV-2 replication in vitro (Caly et al., 2020) . Rajter et al in a retrospective clinical study observed a lower death rate in hospitalized cases (Rajter et al., 2021) . Mahmud et al observed that a combination of ivermectin and doxycycline was effective in patients with mild to moderate COVID-19 (Mahmud et al., 2021) .

Niclosamide is an approved drug for the treatment of tapeworm infection (Zeng et al., 2020) . It works by inhibiting S-phase kinase-associated protein-2 activity by promoting autophagy which results in decreasing coronavirus replication. It may also target SARS-CoV-2 by this mechanism.

At the sub molecular level, niclosamide has been shown to inhibit SARS-CoV-2 (Zeng et al., J o u r n a l P r e -p r o o f 2020). A clinical trial reported that niclosamide has been shown to mitigate cytokine storms in severe COVID-19 patients . Currently, clinical trials are going on for niclosamide against SARS-CoV-2 (Table 1) .

3-chymotrypsin like protease (3CLpro) is a prominent target and exciting prospect for rationalbased antiviral exploration because it controls virus replication (Vandyck et al., 2021) . Protease indicators are indicated generally for other viruses and it is not still FDA-approved for SARS-CoV-2. 3CL pro inhibitors have shown broad-spectrum antiSARS-CoV-2 activity in terms of viral entry through cathepsin L and other host proteases (Mellott et al., 2021) . PF-07321332 from Pfizer is in the clinical trial, a second-generation drug targeting 3CLpro for inhibiting viral replication (Vandyck et al., 2021) .

Nitric oxide (NO) is a vital agent generated endogenously by three enzymes in mammalian cells:

neuronal (n NOS), endothelial (eNOS), and inducible nitric oxide synthase (iNOS) (Chavda et al., 2021e) . NO is a vital element of the lungs and is essential for the regulation of pulmonary vasomotor tone (Mehta and Dhapte-Pawar, 2021) . Inhaled NO therapy is explored for the treatment of acute lung injury, pulmonary hypertension in newborns (PPHN), and ARDS (Bernasconi and Beghetti, 2002) . During SARS-CoV-1 infection, iNOS activity is usually increased, and NO inhibits viral replication by cytotoxic reactions involving the intermediate peroxynitrite (Chavda et al., 2021e; Mehta and Dhapte-Pawar, 2021) . SARS-CoV-2, on the other hand, infects endothelial cells, which are an important source of NO synthesis. As a result, the use of inhaled NO in the treatment of SARS-CoV-2 infections may be effective by restoring J o u r n a l P r e -p r o o f endothelial function and reducing inflammatory responses (Lotz et al., 2021) . It is an important molecule for severe COVID-19 patients where there is a shortage of ventilator 3.2 Potential drugs that act through SARS-CoV-2 uptake pathways in ongoing clinical trials a) Carragelose ® Carragelose ® is a unique, widely active antiviral molecule used to treat a variety of pulmonary diseases (Powell et al., 2017) .In the European Union, Australia, and parts of Asia, Carragelose ® (sulfated polymer) is made from red seaweed algae that have been allowed for use in nasal sprays, throat sprays, and lozenges (Mehta and Dhapte-Pawar, 2021 Tocilizumab was issued to treat rheumatoid arthritis and cytokine release syndrome . It is a humanized recombinant monoclonal antibody (mAb) that binds to the human IL-6 receptor (IL6R) and blocks its signal transduction pathway . It inhibits the IL-6 receptor to mitigate proinflammatory cytokines which are raised during severe COVID-19

conditions (Deb et al., 2021) . A study in China reported successful treatment of the patient with COVID-19 and multiple myeloma when given tocilizumab . After intravenous infusion of tocilizumab, along with other treatments such as lopinavir-ritonavir, a 42-year-old patient from France with COVID-19-related respiratory failure had a fast and favorable result J o u r n a l P r e -p r o o f (Samaee et al., 2020) . Deb et al. evaluated the benefits of tocilizumab in patients with critical COVID-19 (Deb et al., 2021) . A clinical study from Italy recommended tocilizumab for use in critical patients including pneumonia COVID-19 patients or patients in ventilators (Deb et al., 2021) .

Corticosteroids drugs like hydrocortisone, dexamethasone are associated with decreased mortality in viruses like influenza A (Kifle et al., 2021) . Dexamethasone has been reported to improve mortality in severe COVID-19 patients requiring mechanical ventilation when compared with patients with COVID 19 of usual treatment (Group et al., 2021) . Dexamethasone had no improvement in the mortality rate in COVID-19 patients without respiratory assistance (Prescott and Rice, 2020) . Their anti-inflammatory properties can help to minimize systemic inflammation, decrease fluid retention in the lungs, and avoid more alveolar injury, thus improves hypoxia and lowering the risk of respiratory system failure (Kifle et al., 2021) .

Leronlimab, humanized IgG4-κ mAb that binds to the C-C chemokine receptor type 5(CCR5) and

inhibits it (Agresti et al., 2021) .As a result, it reduces proinflammatory cytokines and also preventing Treg(regulatory T cells) from migrating to the infection location. It has shown effectiveness against HIV. A clinical study reported that subcutaneous leronlimab administration was shown to be safe and may have been linked to impressive recovery in four critically ill SARS-CoV-2 patients (NCT04901689).

Infliximab is a chimeric monoclonal anti-TNF antibody (Stallmach et al., 2020) . Stallmach et al. reported that successful treatment in patients with severe COVID-19 and inflammatory bowel disease (IBD) when Infliximab was administered (Stallmach et al., 2020) . TNF, in particular, can aggravate lymphopenia by destroying T cells directly through TNF/TNFR1 signaling, and T cell dysfunction is an essential but underappreciated target for immunomodulatory involvements. So, anti-TNF targets may be encouraging to use in cytokine storm of COVID-19 but its effect can be seen only in severe COVID-19 patients (Stallmach et al., 2020) . The clinical trial is in an ongoing process for infliximab against SARS-CoV-2 (Table 1) .

The antimalarial drug combination artesunate and pyronaridine have had a wide range of the antiviral spectrum (Nair et al., 2021) . Artesunate's antiviral effects against DNA viruses have been well documented, and they tend to be regulated by Sp1 and NF-kB, two proteins that take part in the IFN pathway (Pfeffer, 2011) . Artesunate, in addition to its antiviral properties, has been shown to protect mice from lung damage. Inverno cells study showed the potency of inhibiting replication of SARS-CoV-2 by artesunate and pyronaridine (Nair et al., 2021) .

Gimsilumab, a mAb used in ankylosing spondylitis (Saha et al., 2020) . Granulocyte-macrophage colony-stimulating factor (GM-CSF), an important myelopoietic growth factor, flashed a lot of attention as a potential pharmacological drug that may use in COVID-19 (Lang et al., 2020) . the RBD, the N Terminal Domain (NTD) and the S2 domain. The tripartite binding and RBDindependent neutralization mechanism allow the MP0423 molecule to lose binding to any of its domains while maintaining a high neutralizing potency" (Rothenberger et al., 2021) . Phase 1 trials are ongoing for this novel molecule against SARS-CoV-2 (Table 1) .

reprogramming after SARS-COV-2entry to satisfy the increased demand for nutrients and energy for viral replication, where 2-DG, a glucose antimetabolite, might be a promising therapeutic option since it works as a dual inhibitor of glycolysis and glycosylation (Balkrishna et al., 2020) . J o u r n a l P r e -p r o o f

USFDA follows a systematic approach to combat COVID-19. To date, US-FDA approved only remdesivir drugs to be used in hospitalized COVID-19 patients (Authorization, 2021) . US-FDA patients in the ambulatory setting. Convalescent plasma carrying antibodies of SARS-CoV-2 given to the patients with severe COVID-19 is the treatment approach whose observational data are very encouraging but clinical trials did not prove the evidence (Simonovich et al., 2021) . Many countries grant emergency authorization to convalescent plasma in severe COVID-19 patients based on observational data (Simonovich et al., 2021) . Clinical trial data (NCT04401579) of antiviral drugs (Baricitinib with remdesivir ) compared to remdesivir alone showed that in COVID- (Katz, 2021) J o u r n a l P r e -p r o o f

Vaccines may be the effective means of providing COVID-19 immunity to the majority of people.

However, specific novel anti-SARS-CoV-2 medications are anticipated to play a major role in protecting people who are unvaccinated or immunocompromised, as well as at periods when vaccinations fail to protect against circulating variant virus (Chavda et al., 2021f) . Few novel anti-SARS-CoV-2 molecules are already in clinical trials to target the SARS-CoV-2 virus. Monoclonal antibodies against SARS-CoV-2 are in great interest of research during this pandemic. Monoclonal antibodies target the spike protein of SARS-CoV-2 to neutralize it (Hurt and Wheatley, 2021) .

However, the concern is that the emerging variants like B. Table 3 . Binds to the spike proteins of SARS-CoV-2 and prevents viral entry in a host cell.

Phase 1 COVI-GUARD (STI-1499)

Neutralizing antibody that binds to the S1 subunit of the spike protein in SARS-CoV-2.

J o u r n a l P r e -p r o o f

"Coronavirus Treatment Acceleration Program" (CTAP), developed by the USFDA, is a distinct emergency program for potential coronavirus treatments (Manager et al., 2021) . The program employs any available technique to get novel therapies to patients as soon as possible while still determining whether they are beneficial or detrimental. The FDA continues to fund clinical trials that are evaluating novel COVID drugs to collect useful information on their safety and efficacy (Manager et al., 2021; Rome and Avorn, 2020) . As of Aug 4 2021, under the CTAP program, more than 600 drugs are in the planning stages of drug development programs, FDA, ten number COVID-19 drugs under emergency use authorization, examines more than 400 trials and 1 treatment drug is currently approved by FDA. Furthermore, under CTAP, more than 50 antiviral treatments, more than 40 cells, and gene therapies, more than 130 immunomodulators, more than 50 neutralizing antibodies, more than 110 therapeutics from other pharmacological categories are being studied for COVID-19 treatment. More than 100 and 330 therapeutics are in early-stage (phase 0,1,1/2) and late-stage (phase 2,2/3,3,4) respectively for COVID-19 treatment Manager et al., 2021) .

J o u r n a l P r e -p r o o f

Despite having strong in vitro efficacy against SARS-CoV-2 and clinical results from other human coronaviruses such as SARS and MERS, the repurposed drugs have failed to show efficacy in clinical studies (Indari et al., 2021; Martinez, 2021) . Various clinical trials of repurposed drugs are reported and showed no beneficial effect in COVID-19 (Martinez, 2021) . Some major repurposed drugs used from the beginning of the outbreak of COVID-19 were hydroxycholoroquine and choloroquine, favipiravir, ribavirin, lopinavir-ritonavir, interferons (Martinez, 2021; Vandyck and Deval, 2021) . Based on the data of observational study on few patients and micromolar concentrations in tissue culture, antimalarial drugs like hydroxycholoroquine and chloroquine were used against SARS-COV-2 (Kamat and Kumari, 2021). However, large clinical studies have showed no benefit of hydroxychloroquine and/or chloroquine drugs against COVID-19 in reducing morbidity or mortality (Martinez, 2021) . A prospective clinical trial showed that favipiravir failed to improve SARS-CoV-2 clearance in hospitalized patients (Doi et al., 2020) . A large multicenter retrospective cohort study revealed that there is no clinical benefit of ribavirin/interferons in COVID-19 . No clinical benefit was established when HIV-1 protease inhibitors like lopinavir-ritonavir was used against SARS-CoV-2 (Cao et al., 2020) . Remdesivir, US-FDA approved drug for COVID -19 showed no benefit of mortality in clinical study reported by wang and colleagues (Wang et al., 2020b) . Solidarity trial by WHO also revealed no effect of mortality, period of hospital stay and beginning of ventilation by remdesivir, hydroxychloroquine, lopinavir and interferons therapy in COVID-19 patients (WHO, 2020). However, clinical study in US reported that remdesivir improved clinical outcomes in severe COVID-19 patients . These conflicting results showed that strong evidence is lacking for remdesivir that is to be used in COVID-19. The clinical evidence of the use of ivermectin in COVID-19 is also limited J o u r n a l P r e -p r o o f (Mega, 2020) . Immunomodulators like dexamethasone improved the mortality benefits among severe COVID-19 patients in hospitalized patients of COVID-19 (Martinez, 2021) .

It is reasonable to expect that 80% of those who recovered from COVID-19 of a mildly symptomatic appearance will not have long-lasting consequences and will ultimately improve completely. Patients with a relatively serious symptomatic appearance that needed hospitalization but not artificial ventilation had no mid-term complications . Patients with serious symptomatic presentation who need artificial ventilation likely to experience long-term problems and delayed recovery aging (del Rio et al., 2020) . Changes in the pathophysiology of SARS-CoV-2, inflammatory damage, and immunologic irregularities in COVID-19 are all potential pathways leading to post-COVID-19 complications. The various multiorgan system can be affected in severe COVID-19 survivors (Nalbandian et al., 2021) .

COVID-19 survivors have recorded a wide range of pulmonary symptoms, from dyspnea to complicated fibrotic lung injury and ventilator weaning (Nalbandian et al., 2021) . The most prevalent chronic symptom outside acute COVID-19 is dyspnea, with 42-66 percent prevalence at 60-100 days follow-up, similar to the recovered patients from ARDS of different etiologies.

A tentative finding of an important radiological and symptomatic change in a sample of COVID-19 recovered patients shows that at post-COVID-19, corticosteroid treatment could be effective in a subset of patients (Myall et al., 2021) .ARDS caused by severe COVID-19 and influenza A (H1N1) infection, lung transplantation was previously done for fibro proliferative lung disease (Nalbandian et al., 2021) . Antifibrotic treatments are being tested in clinical trials to suppress pulmonary fibrosis after COVID-19 (Peter M George et al., 2020) . 

The prevalence of venous thromboembolism (VTE) of 5% was reported in the patients recovered from COVID-19 (Nalbandian et al., 2021) . While definitive proof is lacking, provided with sustained primary thromboprophylaxis (up to 45 days), prolonged hospital discharge (up to 6 weeks), and in those managed as outpatients could have a better risk-benefit ratio in SARS-CoV-2 infection (Nalbandian et al., 2021) .Anticoagulation agents such as direct oral anticoagulants and low-molecular-weight heparin are preferred in post-COVID-19 infection (Barnes et al., 2020) .

Similar to triggered VTE, anticoagulation drugs are prescribed for those with imaging-confirmed venous thromboembolism up to 3 months (Bai et al., 2020; Moores et al., 2020) .

J o u r n a l P r e -p r o o f

A Chinese study reported that 20% of COVID-19 recovered patients at 60 days' follow-up documented chest pain while 9% and 5% of COVID-19 recovered patients shown continuing palpitations and chest pain respectively at 6 months follow-up (Carvalho-Schneider et al., 2021; Nalbandian et al., 2021) .

In those with cardiovascular problems after an acute infection or recurrent heart symptoms, assessment with electrocardiogram and echocardiogram for serial clinical and imaging at 4-12 weeks can be considered (Desai et al., 2021; . Abstaining from competitive activities or physical exercise up to 6 months before myocarditis is resolved by cardiac magnetic resonance imaging or troponin normalization is recommended for sportsperson with COVID-19-related cardiovascular complications (Hendren et al., 2020; Maron et al., 2015) . In persons with stable cardiovascular disease, renin-angiotensin-aldosterone system (RAAS) inhibitors are useful and should be sustained, despite initial theoretical worries about the possibility of acute COVID-19 and increased levels of ACE2 and with their use (Hendren et al., 2020; Lopes et al., 2021) . Instead, abruptly stopping RAAS inhibitors may be dangerous (Lopes et al., 2021) .

Low-dose beta-blockers can help patients to regulate their heart rates and diminish adrenergic activity (Raj et al., 2009; Vaduganathan et al., 2020) . The use of medications in patients like antiarrhythmic agents (like amiodarone)with fibrotic pulmonary changes following COVID-19 needs special attention (Lopes et al., 2021; Nalbandian et al., 2021; Raj et al., 2009) .

COVID-19 survivors have documented recurrent malaise, diffuse myalgia, sleep disturbance, and depressive symptoms (Nalbandian et al., 2021; Raj et al., 2009) . Migraine-like headaches and lateonset headaches linked to elevated cytokine levels are other COVID-19 post-acute manifestations J o u r n a l P r e -p r o o f (Arca and Starling, 2020; Belvis, 2020; Nalbandian et al., 2021) . A clinical study reported around 10 % of patients, loss of taste and smell with recurrent headache Nalbandian et al., 2021) . Nearly 30-40% of patients reported clinically severe depression and anxiety (Nalbandian et al., 2021) . For neurologic conditions such as migraine, standard treatments may be used with the consultation of a physician (Do et al., 2019) . In patients with cognitive dysfunction, a neuropsychological assessment should be considered in the post-acute disease environment (Nalbandian et al., 2021) .

Extreme acute kidney injury (AKI)affects 5-6 % of all hospitalized patients with up to 30 % of critically COVID-19 patients which demanding renal replacement therapy (RRT), particularly those with severe infections requiring mechanical ventilation (Robbins-Juarez et al., 2020; Stevens et al., 2020) . Although the prevalence of dialysis-dependent AKI at discharge is poor, the degree of renal function improvement is not surfaced. Therefore, COVID-19 recovered patients with persistently compromised renal function in the post-COVID-19 infectious process can benefit from nephrologists in AKI survivor clinics, which has been linked to better outcomes in the past (Gupta et al., 2020; Nalbandian et al., 2021; Stevens et al., 2020) .

Patients without diabetes mellitus have developed diabetic ketoacidosis weeks to months after the COVID-19 signs have resolved (Sathish and Chandrika Anton, 2021) .COVID-19 can also exacerbate autoimmune thyroid diseases, such as Hashimoto's thyroiditis or Graves' disease (Chng et al., 2018; Mateu-Salat et al., 2020) .

In patients with recently diagnosed diabetes mellitus who do not have typical risk factors for type 2 diabetes, serologic tests for type 1 diabetes-related autoantibodies and repeat post-prandial C-J o u r n a l P r e -p r o o f peptide analyses should be done at follow-up, while it is appropriate to handle patients with such risk factors as if they had ketosis-prone type 2 diabetes (DiMeglio et al., 2018) . Corticosteroids can be used to control hyperthyroidism caused by SARS-CoV-2-related disruptive thyroiditis (Ruggeri et al., 2021) .

COVID-19 can change the gut microbiota, favoring opportunistic infectious agents thus reducing beneficial commensals (Donati Zeppa et al., 2020; Zuo et al., 2020) . The gut microbiota's capacity to influence the progression of respiratory infections (gut-lung axis) has previously been recognized in influenza and other respiratory infections (Bradley et al., 2019) . Faecalibacterium prausnitzii, a butyrate-producing anaerobe associated with good health, was shown to be inversely linked to disease severity in COVID-19 (Miquel et al., 2013; Nalbandian et al., 2021) . Still, clinical research is going on regarding post-COVID-19 effects on gastrointestinal and hepatobiliary systems (Nalbandian et al., 2021) .

Dermatic manifestations of COVID-19 emerged after (64%) or concurrently with (15%) other post-COVID-19 symptoms in a worldwide sample of 716 individuals with COVID-19, with an estimated delay of 7.9 days in adults from the onset of upper respiratory symptoms to dermatologic outcomes (Freeman et al., 2020; Mirza et al., 2021) . In the Chinese trial of recovered COVID-19 patients, only 3% of patients shown skin rash after 6 months . Hair loss was the most common dermatologic complaint, with about 20% of patients reporting it. Hair loss can be caused by telogen effluvium, which is caused by a viral infection or a stress factor. Still, clinical study is going worldwide regarding the effects of post-COVID-19 on dermatologic conditions (Nalbandian et al., 2021; Sun et al., 2021) .

J o u r n a l P r e -p r o o f

Mucormycosis, also known as zygomycosis or phycomycosis, is a rare and deadly fungal illness that mainly affects people who have a compromised immune system (Chavda and Apostolopoulos, 2021; Valour et al., 2014) . The ethmoids are the most often affected sinuses, followed by the maxillary sinus . According to the study, 8% of secondary bacterial or fungal infections were developed among COVID-19 patients or recovered COVID-19 patients while in the hospital, despite extensive usage of steroids and antibiotics (Rawson et al., 2020) . The use of a lot of steroids and broad-spectrum antibiotics to treat COVID-19 might induce or worsen fungal illness . In a study of 135 COVID-19 infected patients, White et al. reported a 26.7 percent incidence of invasive fungal infections .

Once the diagnosis is established, surgical debridement of the fungal-infected region should be undertaken urgently. An intensive surgical method in mucormycosis has a great success rate. To begin, amphotericin-B deoxycholate is the antifungal therapy of choice, with liposomal formulations favored due to lower nephrotoxicity. Posaconazole is a viable alternative to amphotericin treatment in circumstances when it is refractory or intolerant .

MIS-C is defined by the following syndromes such as multiple organ dysfunction, fever, diarrhea, vomiting, dermatological disorders like rashes, increased inflammatory markers with neurological and cardiovascular complications which may happen in children with -post-COVID-19 infection (Morita et al., 2007) . Metanalysis study of children with MIS-C reported a survival rate of91.1%

and a mortality rate of 3.5% . Current treatment of MIS-C includes immunoglobulin I.V., supportive glucocorticoids, and a low dosage of aspirin (Nalbandian et al., 2021) .

J o u r n a l P r e -p r o o f 9. Concluding remarks and future prospects:

The COVID-19 pandemic continues to be a global issue. Although the exceptionally great report of millions of people receiving safe and efficient vaccines every day, the novel coronavirus will continue to spread until global herd immunity is achieved -a goal that may take a long time to achieve. Even then, public health officials will have to be on the lookout for viral alterations. We will be able to effectively control future occurrences if we have numerous reliable medicines in our COVID-19 toolbox. As per USFDA's CTAP, Antivirals drugs, steroids, cell and gene therapies, and mAbs are just a few of the therapeutics that could effectively cure COVID-19.

More than 300 clinical trials are underway in COVID-19 patients to assess the safety and efficacy of various medication options. A swarm of studies published recently in various scientific journals on COVID-19 genesis, pathology, clinical therapies, and drug discovery, as well as repurposing initiatives, are serving as beacons of hope that a vaccine and/or successful treatment may be available soon. Because SARS-CoV-2 targets the respiratory tract, the medicines are administered in non-invasive ways. Because aerosols lacking nano-carriers may be unable to bind to the target, nanocarrier-mediated drug delivery is preferred for effective target binding. Future cellular therapies may also help with COVID-19 treatment. AlloVir and Baylor College of Medicine are collaborating to develop virus-specific T cells (VSTs), which could help in combating a variety of viral infections, including COVID-19.

There are many newer drugs and repurposed drugs being investigated for the COVID-19 treatment since last 2 years. As of December 2021, more than 5782 ongoing clinical trials registered on It should be available as the over the counter drug if possible. This will make the treatment option more patient friendly.

2) Currently, majority of the drugs for COVID-19 management are given by IV route which required trained medical professionals for drug delivery. In order to tackle the pandemic situationthe newer versions of the antiviral should have preferential route of administration either oral (tablet or capsule) or nasal (intranasal spray) for better patient compliance (Chavda et al., 2021e) .

3) The newer versions of the antiviral should have better specificity for the specific viral targets. It is highly desirable that these drugs have sufficient concentration at target side and can easily disrupt the viral replication process. Similarly, viral mutation should also be targeted to get the better efficacy profile as a part of standard treatment. 

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.

Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial

C1 Esterase Inhibition: Targeting Multiple Systems in COVID-19

Favipiravir: A new and emerging antiviral option in J o u r n a l P r e -p r o o f COVID-19

Disruption of CCR5 signaling to treat COVID-19-associated cytokine storm: Case series of four critically ill patients treated with leronlimab

Small-molecule antiviral agents in ongoing clinical trials for COVID-19

Treatment-Refractory Headache in the Setting of COVID-19 Pneumonia: Migraine or Meningoencephalitis? Case Report. SN Compr

Emergency Use Authorization for Vaccines Explained What is an Emergency Use Authorization ( EUA )? Are the COVID-19 vaccines rigorously tested ? What safety and effectiveness data are required to be submitted to FDA for an EUA

Updated guidance on the management of COVID-19: from an

Drug repurposing screens identify chemical entities for the development of COVID-19 interventions

Glucose antimetabolite 2-Deoxy-D-Glucose and its derivative as promising candidates for tackling COVID-19: Insights derived from in silico docking and molecular simulations

Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: interim clinical guidance from the anticoagulation forum

Headaches During COVID-19: My Clinical Case and Review of the Literature

Inhaled nitric oxide applications in paediatric practice

Strategies to DAMPen COVID-19-mediated lung and systemic inflammation and vascular injury

Microbiota-Driven Tonic Interferon Signals in Lung Stromal Cells Protect from Influenza Virus Infection

Treatment of COVID-19 with remdesivir in the absence of humoral immunity: a case report

The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro

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

Follow-up of adults with noncritical COVID-19 two months after symptom onset

COVID-19 : SARS-CoV-2 Variant Classifications and Definitions Variant classifications [WWW Document

Mucormycosis -An opportunistic infection in the aged immunocompromised individual: A reason for concern in COVID-19

A Veterinary Vaccine for SARS-CoV-2: The First COVID-19 Vaccine for Animals

Darunavir ethanolate: Repurposing an anti-HIV drug in COVID-19 treatment

Nucleic Acid Vaccines for COVID-19: A Paradigm Shift in the Vaccine Development Arena

DNA vaccines for SARS-CoV-2: towards third generation vaccination era

Intranasal vaccines for SARS-CoV-2: From challenges to potential in COVID-19 management

COVAX-19Ⓡ Vaccine: Completely blocks virus J o u r n a l P r e -p r o o f transmission to non-immune individuals

A Review of Treatment of Coronavirus Disease 2019 (COVID-19): Therapeutic Repurposing and Unmet Clinical Needs

Diagnostic performance of ATA, BTA and TIRADS sonographic patterns in the prediction of malignancy in histologically proven thyroid nodules

A lesson from a saboteur: High-MW kininogen impact in coronavirus-induced disease 2019

An update to monoclonal antibody as therapeutic option against COVID-19

Long-term Health Consequences of COVID-19

Management of Arrhythmias Associated with COVID-19

Epidemiology of COVID-19

Type 1 diabetes

Red and orange flags for secondary headaches in clinical practice: SNNOOP10 list

A Prospective, Randomized, Open-Label Trial of Early versus Late Favipiravir Therapy in Hospitalized Patients with COVID-19

Gut Microbiota Status in COVID-19: An Unrecognized Player? Front

Bamlanivimab plus Etesevimab in Mild or Moderate Covid-19

Molnupiravir, an Oral Antiviral Treatment for COVID-19

The spectrum of COVID-19-associated dermatologic manifestations: An international registry of 716 patients from 31 countries

Respiratory follow-up of patients with COVID-19 pneumonia

Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy

AT-527, a Double Prodrug of a Guanosine Nucleotide Analog, Is a Potent Inhibitor of SARS-CoV-2 In Vitro and a Promising Oral Antiviral for Treatment of COVID-19

Dexamethasone in Hospitalized Patients with Covid-19

Supplementation with vitamin D in the COVID-19 pandemic?

Description and Proposed Management of the Acute COVID-19 Cardiovascular Syndrome

Rethinking remdesivir for COVID-19: A Bayesian reanalysis of trial findings

2021. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study

Neutralizing Antibody Therapeutics for COVID-19

An Update on Antiviral Therapy Against SARS-CoV-2: How Far Have We Come?

Virtual high throughput screening: Potential inhibitors for SARS-CoV-2 PL(PRO) and 3CL(PRO) proteases

Drugs repurposed for COVID-19 by virtual screening of 6,218 drugs and cell-based assay

COVID-19 and multisystem inflammatory syndrome in children and adolescents

Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis

Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19

Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19

Repurposing Chloroquine Against Multiple Diseases With Special Attention to SARS-CoV-2 and Associated Toxicity

A Little) Clarity on Convalescent Plasma for Covid-19

Ivermectin as a potential drug for treatment of COVID-19: an in-sync review with clinical and computational attributes

Drug Repurposing Approach, Potential Drugs, and Novel Drug Targets for COVID-19 Treatment

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges

GM-CSF-based treatments in COVID-19: reconciling opposing therapeutic approaches

Efficacy of ribavirin and interferon-α therapy for hospitalized patients with COVID-19: A multicenter, retrospective cohort study

Effect of Discontinuing vs Continuing Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers on Days Alive and out of the Hospital in Patients Admitted with COVID-19: A Randomized Clinical Trial

Effects of inhaled nitric oxide in COVID-19-induced ARDS -Is it worthwhile?

Ivermectin in combination with doxycycline for treating COVID-19 symptoms: a randomized trial

Coronavirus Treatment Acceleration Program ( CTAP ) Frequently Asked Questions

Eligibility and Disqualification Recommendations for Competitive Athletes with Cardiovascular Abnormalities: Task Force 3: Hypertrophic Cardiomyopathy, Arrhythmogenic Right Ventricular Cardiomyopathy and

Lack of Effectiveness of Repurposed Drugs for COVID-19 Treatment

SARS-COV-2 as a trigger for autoimmune disease: report of two cases of Graves' disease after COVID-19

Latin America's embrace of an unproven COVID treatment is hindering drug trials

Novel and Evolving Therapies for COVID-19 Related Pulmonary Complications

A Clinical-Stage Cysteine Protease Inhibitor blocks SARS-CoV-2 Infection of Human and Monkey Cells

Faecalibacterium prausnitzii and human intestinal health

Dermatologic manifestations of COVID-19: a comprehensive systematic review

Prevention, Diagnosis, and Treatment of VTE in Patients With Coronavirus Disease

Characterization of the genus Pseudozyma by the formation of glycolipid biosurfactants, mannosylerythritol lipids

Iota-carrageenan neutralizes SARS-CoV-2 and inhibits viral replication in vitro

Interstitial Lung Disease. An Observational Study of Corticosteroid Treatment

Artemisia annua L. extracts inhibit the in vitro replication of SARS-CoV-2 and two of its variants

Omicron Variant: What You Need to Know

The time to offer treatments for COVID-19

Coronavirus (COVID-19) Testing -Statistics and Research -Our World in Data

The role of nuclear factor κB in the interferon response

Antiviral Drugs for Acute Infections

Corticosteroids in COVID-19 ARDS: Evidence and Hope During the Pandemic

Propranolol decreases tachycardia and improves symptoms in the postural tachycardia syndrome: less is more

Use of Ivermectin Is Associated With Lower Mortality in Hospitalized Patients With Coronavirus Disease 2019: The Ivermectin in COVID Nineteen Study

Bacterial and Fungal Coinfection in Individuals With Coronavirus: A Rapid Review To Support COVID-19 Antimicrobial Prescribing

Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing

Ivermectin, antiviral properties and COVID-19: a possible new mechanism of action

Outcomes for Patients With COVID-19 and Acute Kidney Injury: A Systematic Review and Meta-Analysis

Drug Evaluation during the Covid-19 Pandemic

Multi-specific DARPin® therapeutics demonstrate very high potency against mutated SARS-CoV-2 variants in vitro

Subacute thyroiditis in a patient infected with SARS-COV-2: an endocrine complication linked to the COVID-19 pandemic

Repurposing Drugs, Ongoing Vaccine, and New Therapeutic Development Initiatives Against COVID-19

Tocilizumab for treatment patients with COVID-19: Recommended medication for novel disease

Newly diagnosed diabetes in patients with mild to moderate COVID-19

Post coronavirus disease mucormycosis: a deadly addition to the pandemic spectrum

Efficacy and Safety of Favipiravir in Moderate COVID-19 Pneumonia Patients without Oxygen Therapy: A Randomized, Phase III Clinical Trial

Drug repurposing approach to fight COVID-19

Inflammation, immunity and potential target therapy of SARS-COV-2: A total scale analysis review

COVID-19 Drug Therapy What ' s been updated : Highlights

Infliximab against severe COVID-19-induced cytokine storm syndrome with organ failure -A cautionary case series

High rate of renal recovery in survivors of COVID-19 associated acute renal failure requiring renal replacement therapy

Beyond Antibodies: The DARPin® Drug Platform

Characterization and Biomarker Analyses of Post-COVID-19 Complications and Neurological Manifestations

Neutralizing monoclonal antibodies for treatment of COVID-19

Genomic evidence for reinfection with SARS-CoV-2: a case study

Renin-Angiotensin-Aldosterone System

Actinomycosis: etiology, clinical features, diagnosis, treatment, and management

CoV-2 3-chymotrypsin-like cysteine protease inhibitor exhibits in vivo efficacy in a Syrian Hamster model

Considerations for the discovery and development of 3-chymotrypsin-like cysteine protease inhibitors targeting SARS-CoV-2 infection

SARS-CoV-2 RNA-dependent RNA polymerase as a therapeutic target for COVID-19

COVID-19 drug repurposing: A review of computational screening methods, clinical trials, and protein interaction assays

Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial

Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial

REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19

A national strategy to diagnose COVID-19 associated invasive fungal disease in the ICU

Repurposed Antiviral Drugs for Covid-19 -Interim WHO Solidarity Trial Results

World Health Organization, 2021. COVID-19 Weekly Epidemiological Update 22

World Health Organization (WHO), 2021. WHO-COVID-19-global-data

An Update on Current Therapeutic Drugs Treating COVID-19

Repurpose Open Data to Discover Therapeutics for COVID-19 Using Deep Learning

Extrapulmonary complications of COVID-19: A multisystem disease?

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

Alterations in Gut Microbiota of Patients With COVID-19 During Time of Hospitalization. Gastroenterology