Corona virus disease 2019 (COVID-19) caused by a novel single-stranded RNA coronavirus has swept the world. The International Committee on Taxonomy of Viruses (ICTV) named the virus SARS-CoV-2. The life cycle of SARS-CoV-2 consists mainly of viral attachment, membrane fusion, genome duplication and virion assembly and release. The current drug R&D for SARS-CoV-2 targets one or more events in the viral life cycle to prevent viral replication, such as blocking the binding of spike proteins to angiotensin-converting enzyme 2 (ACE2) and inhibiting viromembrane fusion with host cells or inhibiting 3CL-likeprotease (3CLpro) and papain (PLpro) or inhibiting RNA-dependent RNA polymerase (RdRp). At present, several therapeutic drugs have entered phase III clinical trials suggesting a breakthrough in oral small molecule drugs for SARS-CoV-2.
RNA polymerase (RdRp) inhibitors
1. Molnupiravir
Molnupiravir (MK-4482, EIDD-2801), approved for marketing by the UK Medicines and Healthcare Products Regulatory Agency (MHRA) on November 4, 2021, is the first oral inhibitor of RdRp for the treatment of mild to moderate COVID-19 infections in adults. Molnupiravir has demonstrated superior therapeutic effect and safety in the entire clinical trials (Phases I-III: NCT04392219, NCT04405570, NCT04405739, NCT04939428, NCT04575597, NCT04575584) in patients with COVID-19. The antiviral efficacy of molnupiravir in SARS-CoV-2-infected Vero cells was approximately EC50=0.3 μmol/L, and its antiviral replication potency in human respiratory epithelia was EC50=0.14 μmol/L. It is shown by in vitro toxicity data that a CC50 >10 μmol/L against Vero cells takes an ideal safe window for toxicity and efficacy so molnupiravir is selected as a clinical candidate compound. In the pharmacodynamic mechanism research, scientists found that molnupiravir can effectively insert into the RNA membrane of SARS-CoV-2 virus to promote mutation and end viral replication. It showed by preclinical data in cell culture that the number of viral RNAs with G to A and C to U transition mutations increased in a dose-dependent manner upon molnupiravir, which positively associated with the anti-coronaviral efficacy of molnupiravir. And molnupiravir is categorized as a mutagenic nucleotide analogue. With the RdRp protease purified by SARS-CoV-2, combined with the evaluation of viral RNA replication tests, the researchers investigated the potential biochemical mechanism of the drug, namely the metabolism of molnupiravir as a prodrug in plasma to N 4-Hydroxycytidine (EIDD-1931). As the active subject molecule, EIDD-1931 enters the host infected cells and is phosphorylated by kinase to form N-hydroxycytidine triphosphate as the active component of the drug, which participates in the process of viral RNA replication and induces the production of RNA replication mutants, ultimately leading to the termination of viral replication.
Phase II clinical results from Merck in March 2021 showed that patients with COVID-19 treated with the drug from day 5 achieved a 0% positive virus detection rate in all dose groups (compared to 24% in the placebo group) By the latest phase III clinical results, both indicators of mortality risk and hospitalization risk were reduced by 50% in molnupiravir subjects. The probability of hospitalization or death on day 29 after randomization grouping was 7.3% in patients treated with molnupiravir compared to 14.1% in placebo-treated patients. In terms of safety, the rate of subjects discontinuing treatment due to drug-related adverse events was approximately 1.3% in the molnupiravir-treated group compared with the rates of adverse reactions of any grade in the treatment and placebo groups were 35% and 40%.
2. Remdesivir
Remdesivir (GS-5734) is a nucleoside analogue precursor drug being developed by Gilead Sciences, Inc. that is obtained from a ribose derivative synthesized in a multi-step reaction and effectively binds to the nascent RNA chain via RdRp, resulting in premature termination of viral replication. Remdesivir has a broad-spectrum antiviral activity against various viruses of the family Viridae, including filoviruses and coronaviruses, with half-maximal effect concentration (EC50) values ranging from 0.0035 to 0.75 μmol-L-1. It has demonstrated by in vitro tests that the remdesivir has effective antiviral activity against SARS-CoV-2. Remdesivir is readily recognized in plasma by intravenous administra...
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