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'.

 

[Andrew Mason]

As someone with a long held interest in, but no academic background in, molecular biology, I find this is helpful. I became interested in the idea of using polymerase inhibitors to prevent the SARS-CoV-2 virus from replicating and started this thread in June of 2020 on Remdesivir as well as a later thread on antiviral drugs generally.

The concept is rather simple: in order to replicate, the virus needs the polymerase molecule (RNA dependent RNA Polymerase - RdRp - in the case of SARS-CoV-2) to transcribe its RNA genome and correctly produce the RNA segments that the host cell will translate into viral proteins and other molecules that are then assembled to make another virus. If you can insert into that RdRp molecule a nucleotide that causes it to stop transcription early so that the mRNA sequence is defective, the virus will will not be able to reproduce. Remdesivir inserts a monophosphate molecule into the RdRp at a certain point that causes the RdRp to stop transcription early.

The key, it seems to me, is getting that error inducing molecule inserted into the viral polymerase of a large enough number of viruses to slow the overall replication rate so that the immune system is not overwhelmed and can do its job attacking the virus and ending its spread. I am not sure of this and would invite anyone with expertise in this area to comment.

For HIV, anti-virals are extremely important because the virus attacks the immune system T cells that regulate and conduct the immune response. So the drugs have to control HIV enough so that there are enough healthy T cells to have a functional immune system. It appears that no single anti-viral drug will stop viral replication completely. The approach taken to successfully control HIV replication has been to use several drugs that attack HIV at different stages of replication. One of these is a polymerase inhibitor¹.

But for viruses that do not attack the immune system, the anti-viral drug is not intended as a cure but as a means of slowing viral replication enough so that the immune system can keep up. As I say, that may be just my incorrect understanding.

^1. In HIV this is an RNA-dependent DNA polymerase (Reverse Transcriptase) inhibitor. (The HIV RNA genome is reverse-transcribed to create strands of DNA which are then used by the host cell to transcribe into functional RNA to produce the molecules that make up a new virus copy).

Other HIV antivirals include protease inhibitors to inhibit protein synthesis, cell entry inhibitors that prevent HIV from getting to the T cells, Integrase Strand Transfer Inhibitors that don't block entry but prevent the viral genome from integrating with the host T cell machinery.

AM