Development, repurposing, and characterization of therapeutics for SARS-CoV-2 is an ongoing process. Treatment measures may be broadly categorized into two classes. The first includes a variety of drugs that boost the host antiviral response and/or address a dysregulated inflammatory response (partially reviewed here¹). The second includes virus-targeted compounds that directly interfere with viral replication, which may be further sub-divided according to mechanism(s) of action or viral protein target(s). Whilst several compounds are undergoing pre-clinical evaluation^2,3 , compounds with widespread emergency use authorization (EUA) or higher approval are discussed below. The evolving recommendations for several major medical associations may be accessed for FDA⁴, EMA⁵, and WHO⁶ -specific information. 

Nucleoside Analogues

Remdesivir (Veklury, Gilead Sciences) was developed in 2009 and is effective against a variety of RNA viruses in vitro. Remdesivir is a prodrug whose active metabolite serves as an adenosine analogue. Incorporation of this metabolite by the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) catalytic subunit (nsp12) results in delayed chain termination and/or lethal mutagenesis and may circumvent the actions of the viral exonuclease proofreading complex (nsp10/nsp14). Resistance mutations in the RdRp are generated in vitro, but rarely in clinical application. Such mutations tend to negatively affect proofreading functions and RNA template binding, and they may result in a less fit virus⁷. Remdesivir is administered intravenously in a medical setting, which may limit its clinical efficacy and usage to hospitalized patients. While this compound is currently FDA approved, recommendations for usage continue to evolve among various countries and medical agencies.

Molnupiravir (Merck) was initially developed in 2014 as an inhibitor of multiple RNA viruses including influenza viruses and later repurposed for SARS-CoV-2 treatment. Molnupiravir is a prodrug whose active metabolite serves as either a cytosine or uracil analogue, and it has a similar protein target and mechanism of action as remdesivir. Resistance markers associated with reduced molnupiravir efficacy are not identified in vitro or in treated patients⁸, though further monitoring should continue. Molnupiravir is administered orally for established infections. While this route may increase its clinical use, potential toxicity and off-target effects are not yet fully defined.

Protease Inhibitors

Ritonavir and Nirmatrelvir (Paxlovid, Pfizer) are two separate drugs of the protease-inhibitor class, administered in combination. Nirmatrelvir targets the main SARS-CoV-2 protease (M^Pro/nsp5), inhibiting cleavage of the viral polyprotein, preventing production of subsequent viral proteins, and ultimately halting replication. Ritonavir is an HIV-1 protease inhibitor with no direct SARS-CoV-2 activity, but it instead increases serum-concentrations of nirmatrelvir by slowing its metabolism and increasing its therapeutic efficacy. This ‘boosting’ activity has been described for other HIV protease inhibitors combinations. Both drugs are administered orally. Antiviral resistance to nirmatrelvir is not well defined, but M^Pro substitutions at A260 were infrequently identified in clinical trials and circulating viruses. However, this substitution does not decrease M^Pro activity in virus-free assays⁹.

Antibody Therapies

Convalescent Sera may serve an important early role in combating viral outbreaks, and it was used and studied early in the SARS-CoV-2 pandemic. Though this type of treatment can be associated with antibody-dependent cytotoxicity (ADC), this was not generally observed in early trials during the pandemic. However, the use and efficacy of this treatment in severe infections, where antibody loads are generally very high, is cause for concern¹⁰. Additionally, uncertainties over dosage and intravenous/infusion routes of administration also hinder usage. While continued study of all these aspects continues, treatment with convalescent sera remains under emergency use by some medical agencies including the FDA.

Monoclonal Antibodies (mAbs) are a logical extension of convalescent sera usage, with the ability to identify and expand highly reactive SARS-CoV-2 Spike (S)-targeted antibodies from human donors that can be further refined and re-engineered ex-vivo. Multiple epitopes of the S receptor binding domain (RBD) are targeted by current mAbs. Routes of delivery are intravenous or subcutaneous dose with one or a combination of two mAbs: sotrovimab (Xevudy, GSK), bamlanivimab + etesevimab (Eli Lilly), casirivimab + imdevimab (REGEN-COV, Regeneron), tixagevimab + cilgavimab (Evusheld, AstraZeneca). Resistance can occur through mutation of the RBD and has impacted the use of some mAbs against SARS-CoV-2 variants^10,11. Efficacy of bamlanivimab/etesevimab and casirivimab/imdevimab cocktails are negatively impacted by the omicron (B.1.1.529) and associated sub-variants currently predominating in circulation, while tixagevimab/cilgavimab and sotrovimab retain omicron neutralizing capacity in vitro¹². Some medical agencies, including the FDA, have issued EUA for pre- and post-exposure prophylaxis for some mAb candidates.

1. Robinson PC, Liew DFL, Tanner HL, et al. COVID-19 therapeutics: Challenges and directions for the future. Proc Natl Acad Sci U S A 2022; 119(15): e2119893119.

2. Xiang R, Yu Z, Wang Y, et al. Recent advances in developing small-molecule inhibitors against SARS-CoV-2. Acta Pharm Sin B 2021. 

3. Cully M. A tale of two antiviral targets - and the COVID-19 drugs that bind them. Nat Rev Drug Discov 2022; 21(1): 3-5. 

4. National Institutes of Health. Characteristics of SARS-CoV-2 Antibody-Based Products. 2022.

5. European Medicines Agency. COVID-19 treatments. 2022.

6. World Health Organization. Therapeutics and COVID-19: living guideline. 2022.

7. Focosi D, Maggi F, McConnell S, Casadevall A. Very low levels of remdesivir resistance in SARS-COV-2 genomes after 18 months of massive usage during the COVID19 pandemic: A GISAID exploratory analysis. Antiviral Res 2022; 198: 105247.

8. Malone B, Campbell EA. Molnupiravir: coding for catastrophe. Nat Struct Mol Biol 2021; 28(9): 706-8. 

9. Lamb YN. Nirmatrelvir Plus Ritonavir: First Approval. Drugs 2022.

10. Lee WS, Wheatley AK, Kent SJ, DeKosky BJ. Antibody-dependent enhancement and SARS-CoV-2 vaccines and therapies. Nat Microbiol 2020; 5(10): 1185-91.

11. Li D, Sempowski GD, Saunders KO, Acharya P, Haynes BF. SARS-CoV-2 Neutralizing Antibodies for COVID-19 Prevention and Treatment. Annu Rev Med 2022; 73: 1-16.

12. National Institutes of Health. Anti-SARS-CoV-2 Antibody Products. 2022.

Prepared by: Dr Jeremy C. Jones, Department of Infectious Diseases, St Jude Children’s Research Hospital, Memphis, TN, USA