Metabolism Pathways of Major Therapeutics for Treating Monkeypox Mono- and Co-infection with Human Immunodeficient Virus or SARS-CoV-2.

Monkeypox is a zoonotic viral disease and remains endemic in tropical regions of Central and West Africa. Since May of 2022, cases of monkeypox have soared and spread worldwide. Confirmed cases have shown no travel history to the endemic regions as seen in the past. The World Health Organization declared monkeypox a global public health emergency in July 2022, and the United States government followed suit one month later. The current outbreak, in contrast to traditional epidemics, has high coinfection rates, particularly with HIV (human immunodeficiency virus), and to a lesser extent with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the pathogen of COVID-19. No drugs have been approved specifically for monkeypox. However, there are therapeutic agents authorized to treat monkeypox under the Investigational New Drug protocol, including brincidofovir, cidofovir, and tecovirimat. In contrast to limited options for monkeypox treatment, there are available drugs specifically for HIV or SARS-CoV-2 infection. Interestingly, these HIV and COVID-19 medicines share metabolism pathways with those authorized to treat monkeypox, par¬ticu¬larly of hydrolysis, phospho¬rylation, and active membrane transport. This review discusses how these pathways shared by these medicines should be considered to gain therapeutic synergy and maximize safety for treating monkeypox coinfections.

Viral target and metabolism-based rationale for combined use of recently authorized small molecule COVID-19 medicines: Molnupiravir, nirmatrelvir, and remdesivir.

The COVID-19 pandemic remains a major health concern worldwide, and SARS-CoV-2 is continuously evolving. There is an urgent need to identify new antiviral drugs and develop novel therapeutic strategies. Combined use of newly authorized COVID-19 medicines including molnupiravir, nirmatrelvir, and remdesivir has been actively pursued. Mechanistically, nirmatrelvir inhibits SARS-CoV-2 replication by targeting the viral main protease (Mpro ), a critical enzyme in the processing of the immediately translated coronavirus polyproteins for viral replication. Molnupiravir and remdesivir, on the other hand, inhibit SARS-CoV-2 replication by targeting RNA-dependent RNA-polymerase (RdRp), which is directly responsible for genome replication and production of subgenomic RNAs. Molnupiravir targets RdRp and induces severe viral RNA mutations (genome), commonly referred to as error catastrophe. Remdesivir, in contrast, targets RdRp and causes chain termination and arrests RNA synthesis of the viral genome. In addition, all three medicines undergo extensive metabolism with strong therapeutic significance. Molnupiravir is hydrolytically activated by carboxylesterase-2 (CES2), nirmatrelvir is inactivated by cytochrome P450-based oxidation (e.g., CYP3A4), and remdesivir is hydrolytically activated by CES1 but covalently inhibits CES2. Additionally, remdesivir and nirmatrelvir are oxidized by the same CYP enzymes. The distinct mechanisms of action provide strong rationale for their combined use. On the other hand, these drugs undergo extensive metabolism that determines their therapeutic potential. This review discusses how metabolism pathways and enzymes involved should be carefully considered during their combined use for therapeutic synergy.

The nucleoside antiviral prodrug remdesivir in treating COVID-19 and beyond with interspecies significance.

Infectious pandemics result in hundreds and millions of deaths, notable examples of the Spanish Flu, the Black Death and smallpox. The current pandemic, caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), is unprecedented even in the historical term of pandemics. The unprecedentedness is featured by multiple surges, rapid identification of therapeutic options and accelerated development of vaccines. Remdesivir, originally developed for Ebola viral disease, is the first treatment of COVID-19 (Coronavirus disease 2019) approved by the United States Food and Drug Administration. As demonstrated by in vitro and preclinical studies, this therapeutic agent is highly potent with a broad spectrum activity against viruses from as many as seven families even cross species. However, randomized controlled trials have failed to confirm the efficacy and safety. Remdesivir improves some clinical signs but not critical parameters such as mortality. This antiviral agent is an ester/phosphorylation prodrug and excessive hydrolysis which increases cellular toxicity. Remdesivir is given intravenously, leading to concentration spikes and likely increasing the potential of hydrolysis-based toxicity. This review has proposed a conceptual framework for improving its efficacy and minimizing toxicity not only for the COVID-19 pandemic but also for future ones caused by remdesivir-sensitive viruses.