Viral (RNA and DNA) polymerases, inhibitors and antiviral drugs

[Astronuc]

I stumbled across this article, "Novel derivatives of brincidofovir and (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine inhibit orthopoxviruses and human adenoviruses more potently than brincidofovir"
https://pmc.ncbi.nlm.nih.gov/articles/PMC11985979/

Viral polymerases are the most sought-after targets for developing antiviral drugs. Few dozens of viral RNA or DNA dependent polymerase inhibitors have been licensed for the treatment of human viral diseases, including brincidofovir (BCV), a prodrug of cidofovir (CDV), which is the second FDA approved drug for the treatment of smallpox infection. Given that variola and MPXV are phylogenetically similar, the U.S. CDC suggests that BCV can be requested for the treatment of human Mpox disease in adults and pediatric patients through single-patient FDA emergency use Investigational New Drug (e-IND) for Mpox disease.

I was curious about (3-hydroxy-2-phosphonylmethoxypropyl)

Given that monkeypox virus (MPXV), variola and other emerging orthopoxviruses are posing serious threats to global health, it is urgent to develop better therapeutics. In this study, we tested the antiviral effects of three novel prodrugs, which were designed based on previously reported parent drugs, either (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine ((S)-HPMPC, cidofovir) or (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine ((S)-HPMPA). We found that one of the (S)-HPMPA-based prodrugs, ODE-(S)-HPMPA formate, exhibited significantly better anti-orthopoxvirus activity than BCV both in vitro and in vivo, which also inhibited human adenovirus type 2 and type 21 more efficiently than BCV.

I also found a related article in the context of anitviral polymerase inhibitors: Progression of Antiviral Agents Targeting Viral Polymerases
https://pmc.ncbi.nlm.nih.gov/articles/PMC9654062/

and another "Small Molecule Drugs Targeting Viral Polymerases"
https://www.mdpi.com/1424-8247/17/5/661

Currently, approved polymerase inhibitors are available for nine human viruses, encompassing herpes simplex virus (HSV), varicella-zoster virus (VZV), human cytomegalovirus (HCMV), hepatitis C virus (HCV), influenza virus (Flu), respiratory syncytial virus (RSV), hepatitis B virus (HBV), human immunodeficiency virus (HIV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Table 1). These viruses can be classified based on their genetic material in DNA viruses (HCMV, HSV, VZV, and HBV) and RNA viruses (HCV, RSV, Flu, Ebolavirus, HIV, and SARS-CoV-2). Among them, three viruses encode for a DNA-dependent DNA polymerase (DdDp)—HCMV, HSV, and VZV—while five utilize an RNA-dependent RNA polymerase (RdRp)—HCV, RSV, influenza virus, Ebolavirus, and SARS-CoV-2. Conversely, HIV and HBV employ an RNA-dependent DNA polymerase (RdDp) for genome replication. While DdDp and RdRp copy the genetic material by using DNA and RNA as template, respectively, RdDp initiates DNA synthesis from RNA, utilizing its retroviral enzymatic activity.

Polymerase inhibitors were mentioned in the development of Remdesivir: Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency
https://pmc.ncbi.nlm.nih.gov/articles/PMC7242698/

Mechanism of SARS-CoV-2 polymerase stalling by remdesivir
https://www.nature.com/articles/s41467-020-20542-0

Remdesivir Strongly Binds to RNA-Dependent RNA Polymerase, Membrane Protein, and Main Protease of SARS-CoV-2: Indication From Molecular Modeling and Simulations
https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.710778/full

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Remdesivir: an early repurposed RNA-dependent RNA polymerase inhibitor for treating COVID-19
https://www.sciencedirect.com/science/chapter/edited-volume/abs/pii/B9780443338854000184 (requires subscription or purchase)

Abstract​

Remdesivir (GS-5734), a viral RNA-dependent RNA polymerase (RdRP) inhibitor, has been identified as a promising treatment option for a variety of RNA virus infections. It has gained significant attention as a potential therapeutic for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). On May 1, 2020, the US Food and Drug Administration (FDA) issued Emergency Use Authorization (EUA) for remdesivir to be administered to COVID-19 patients. This review provides a comprehensive assessment of remdesivir’s significance in the fight against the COVID-19 pandemic, covering its developmental milestones, intellectual property considerations, antiviral mechanisms, as well as preclinical research, clinical trials, and detailed information on its pharmacodynamics and pharmacokinetics.

Remdesivir: A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19
https://pmc.ncbi.nlm.nih.gov/articles/PMC7202249/

The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus
https://www.jbc.org/article/S0021-9258(17)48574-7/fulltext

Another anti-viral compound for treating SARS-Cov-2 (and possibly the next SARS-Cov-3) is Paxlovid (Nirmatrelvir/Ritonavir)
Paxlovid: Mechanism of Action, Synthesis, and In Silico Study
https://pmc.ncbi.nlm.nih.gov/articles/PMC9283023/

The first artlcle lead me to discover others, and generically, the trend in developing viral polymerase inhibitors. Some inhibitors seem to work on several viruses, will some viruses seem to require a custom inhibitor. There appears to be significant research efforts in this area.

PF has a number of threads on specific polymerase inhibitors and/or their applications, especially since 2020 and the SARS-Cov-2 (Covid-19) Pandemic. (See Similar Threads below). I also found other threads by searching 'polymerase', or 'Antiviral Polymerase'.