September 25, 2022

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Types and mechanisms of action of new coronavirus antiviral drugs

Types and mechanisms of action of new coronavirus antiviral drugs



 

Types and mechanisms of action of new coronavirus antiviral drugs.

In the early days of the 2020 SARS-Cov-2 virus-induced COVID-19 outbreak, researchers were just beginning to think that the evolution of the SARS-Cov-2 virus’ genome diversity was slow.

However, with the spread of the COVID-19 epidemic, mutant strains of the SARS-Cov-2 virus began to appear around the world.

These mutations are harmless or slightly beneficial to the SARS-Cov-2 virus, such as mutations leading to enhanced transmissibility and virulence and immune escape.

The first discovered mutation in the SARS-Cov-2 virus genome was the Spike protein D614G , which led to more efficient spread of the virus, making the mutant quickly become the main infectious strain worldwide.

There are 5 mutant strains identified so far, namely Alpha, Beta, Gamma, Delta, Omicron, and they all have their own typical mutation sites .

Overall, Spike proteins are particularly prone to accumulating mutations , and these mutants also have mutations associated with host immune escape.


Types and mechanisms of action of new coronavirus antiviral drugs
COVID-19 mutant Spike protein mutation site

 


Many vaccines are currently being developed based on the Spike protein , and population vaccination programs for such vaccines are advancing at full speed.

However, both real-world and serological data suggest that Omicron can escape immunity in both vaccinated and previously infected hosts .

In the face of mutant strains whose transmission ability and immune escape ability are continuously improved, the role that existing vaccines can play in resisting the invasion of virus mutant strains is constantly being weakened.

There are always people who better than you. Once the virus breaks through the human immune system, we must have other killers to stop the virus from multiplying in the body.

Fortunately, researchers have developed several antiviral drugs that have been approved or are in clinical research.

 

Anti-disease drugs can be divided into two categories: neutralizing antibodies targeting the S protein and small-molecule drugs that interfere with viral replication.

 

 

 

COVID-19 neutralizing antibody drug

 

Antiviral mechanism of COVID-19 neutralizing antibody

Humanized monoclonal antibodies capable of neutralizing mutant SARS-Cov-2 strains, which primarily target the SARS-Cov-2 virus, have become a very attractive treatment for 2019-nCoV due to their high specificity and reliability Receptor-binding domain ( RBD ) or N- terminal domain ( NTD ) of Spike protein .

The Spike protein is composed of three identical monomers, consisting of S1 subunit and S2 subunit, which can bind to ACE2 receptors on human epidermal cells and mediate membrane fusion and entry between viruses and host cells.

The S1 subunit domain includes NTD and RBD, and the S2 subunit domain includes FP, HR1, HR2, TM, CP . RBD-specific mAbs can bind to the RBM motif ( receptor-binding motif ) in the RBD domain of Spike protein .

The RBM is responsible for the initial binding of the virus to the host cell ACE2, which initiates the entry of the virus into the cell.

RBD-specific monoclonal antibody can block the interaction of RBM-ACE2 and is a blocker of ACE2.

 

COVID-19 Spike protein structure


Spike proteins exist in different conformations in the host cell, and these conformations are named according to the position of the RBD ( up or down ) .

According to the different conformational RBDs that mAbs bind to, they can be divided into 4 types ( I, II, III, and IV ).

Class I NAbs can only recognize “up” RBDs, class II NAbs or class III NAbs can recognize “up or down” RBDs, and class IV NAbs can bind to conserved regions of RBDs (core I region) or “up” RBDs ( core II region).

Class IV core I region-dependent NAbs have a very broad spectrum of activity against SARS-Cov-2 original strains, mutant strains, and other related coronaviruses.

 

Types and mechanisms of action of new coronavirus antiviral drugsSpike protein structure, conformation, and RBD-dependent mAbs

 


Status of research and development of COVID-19 neutralizing antibodies

On December 8, 2021, AstraZeneca announced that its long-acting novel coronavirus neutralizing antibody Evusheld ( AZD7442 ) was granted an Emergency Use Authorization ( EUA ) by the U.S. FDA .

Evusheld, a combination of two long-acting monoclonal antibodies, is the only antibody therapy authorized in the U.S. for pre-exposure prophylaxis against COVID-19, and the only COVID-19 antibody administered intramuscularly (150mg tixagevimab and 150mg cilgavimab). 

Due to the high production cost, neutralizing antibodies are not suitable for popularization and promotion.

They can only be applied to certain groups of people in specific scenarios, such as a group of people with low immunity, the elderly with underlying diseases, or breakthrough infections. , or pre-exposure prophylactic treatment, etc.

More importantly, most of the current neutralizing antibody drugs are not sensitive to Omicron mutants, and it is difficult to show good clinical effects.

 

 

COVID-19 Small Molecule Drugs

 

1. RNA polymerase inhibitors

Among various RNA virus genes, the only common gene product is RNA-dependent-polymerase ( RdRp ).

In addition, human RNA polymerase does not have RNA polymerase activity that depends on RNA templates, which prevents small molecule drugs targeting viral RdRp from interfering with the normal physiological response of host cells. Therefore , RdRp becomes an ideal antiviral drug target .

 

The SARS-Cov-2 RdRp inhibitor acts as a competitive substrate for NTP and is inserted into the viral RNA sequence under the action of viral RNA polymerase.

In general, RdRp inhibitors can be found by testing nucleotide analog inhibitors. However, because the RdRp structures of different RNA viruses are significantly different, many studies have shown that existing antiviral drugs that can inhibit other viruses have no inhibitory effect on SARS-Cov-2.

 

From another point of view, compared with DNA viruses, RNA virus polymerases have a relatively high polymerization error rate and lack proofreading capability .

The high-frequency error rate will bring many mutations to each round of replication of the viral genome, and the variability of these viral genomes, in turn, improves the virus’s adaptability.

However, there are also special cases where the coronavirus possesses a 3′-5′ exonuclease ( NSP14 ) with a corrective function, which is used to ensure low error rate and high replication fidelity of the viral genome.

NSP14 is especially important because evasion of NSP14’s corrective mechanisms is required for efficient binding of nucleoside analogs to the viral genome. The unique exonuclease activity of coronavirus also brings challenges to the development of antiviral drugs.

 

Types and mechanisms of action of new coronavirus antiviral drugsTarget selection of small molecule drugs in the life cycle of 2019-nCoV

 


Molnupiravir-induced hypermutation

In September 2021, Kabinger et al. published an article in Nat Struct Mol Biol : Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis , and discovered the mechanism by which Molnupiravir causes high frequency mutation of SARS-Cov-2 RNA products .

The active form of Molnupiravir is NHC triphosphate (‘MTP’). SARS-Cov-2 virus RdRp can use NHC as a substrate to replace cytosine triphosphate nucleotides or uracil triphosphate nucleotides.

Next, when the SARS-Cov-2 virus RdRp uses RNA mixed with MTP as a template, NHC in the RNA template sequence will mediate the insertion of G or A into the template to pair with it, resulting in a highly mutated RNA product that cannot form a functional virus. particles.

Fortunately, NHC was able to escape the corrective action of the SARS-Cov-2 exonuclease without being excised.

 

Molnupiravir mechanism of action

 


Molnupiravir was developed by Merck in the United States in conjunction with other companies .

Early clinical data showed that Molnupiravir could reduce the number of hospitalizations and deaths from the COVID-19 by 50% , and there were no patient deaths in the administration group .

On November 4, 2021 , the UK Food and Drug Administration approved the world’s first oral drug for COVID-19, Molnupiravir, for specific populations.

 

Molnupiravir clinical data

 


AT-527 – Chain Termination

 

AT-527 was developed by Atea Corporation of the United States using its unique purine nucleotide prodrug platform.

On October 9, 2021, the company released clinical phase 2 data and failed to achieve the expected results .

 

In February 2022 , Ashleigh Shannon et al. published an article in Natrue Communications : A dual mechanism of action of AT-527 against SARS-CoV-2 polymerase , which found that AT527 has two targets, at the RdRp and NiRAN active sites It has dual inhibitory effects , indicating that it is a very potential small molecule drug against SARS-CoV-2, which can greatly avoid the development of drug resistance.

The active form of AT527 entering cells is AT-9010, which inhibits two independent activities of the SARS-CoV-2 replicase/transcriptase complex.

First, AT-9010 inserts into the 3′ end of the RNA product strand at the RdRp active site, and its chemically modified ribose sugar prevents NTP entry, and the second AT-9010 causes rapid termination of RNA synthesis.

The second, competing with native NTP, binds AT-9010 to the N-terminal domain of nsp12 (NiRAN) active site, acts as a nsp8 and nsp9 NMPylation inhibitor, and inhibits the nucleotidyl transferase activity of NiRAN. nsp12 is a highly conserved gene that does not change with the emergence of mutations and mutant strains.

 

Types and mechanisms of action of new coronavirus antiviral drugsAT-527 has dual targets and inhibits viral replication

 


2. Protease inhibitors

The SARS-CoV-2 viral genome contains many structural proteins (e.g. Spike protein), non-structural proteins (e.g. 3-chymotrypsin-like protease (3CL or major protease Mpro), papain-like protease (PLpro), helicase and RNA-dependent RNA polymerase) and accessory proteins.

The SARS-Cov-2 virus can encode two polypeptides, followed by two viral proteases, PLpro and Mpro , which can process these two polypeptides to catalyze the release of their own and other non-structural proteins to construct viral replication and transcription complexes. This makes Mpro a very attractive drug target .

In addition, among different coronaviruses, Mpro is highly conserved in structure and does not have its homologues in humans, which provides very favorable conditions for the design of Mpro-targeting SARS-CoV-2 inhibitors.

 

PF-07321332/PAXLOVID

PF-07321332, which is a covalent inhibitor , can directly bind to the cysteine ​​catalytic residue ( Cys145 ) of protease .

The success of this drug is still due to the accumulation of Pfizer in the field of drug development over the years . When SARS broke out in 2003, Pfizer developed PF-00835231, a drug targeting SARS virus protease.

However, due to the rapid dissipation of the SARS epidemic, the drug did not conduct follow-up clinical research and was once shelved. After the outbreak of the COVID-19, Pfizer decided to develop a protease inhibitor targeting the SARS-Cov-2 virus, so it picked up PF-00835231 again.

However, since PF-00835231 is a polypeptide-based small molecule drug, it is shown to be rich in hydrogen bonds and polar, and cannot be absorbed by the intestinal tract through oral administration.

Therefore, after a series of complex chemical modifications, the Pfizer R&D team synthesized a series of derived compounds, and finally selected PF-07321332 and used it in combination with the HIV antiviral drug Litonavir.

The combined preparation of the two is called PAXLOVID . Although ritonavir has no anti-new coronavirus activity, it can be combined with liver drug enzymes to prevent PF-07321332 from being metabolized by the liver and losing its activity.

 

In November 2021, Pfizer announced results from a Phase 2/3 trial that were in line with expectations. Results showed that PAXLOVID reduced hospitalization rates by 89 percent when treated within three days of symptom onset .

The drug was approved by the U.S. Food and Drug Administration for emergency use on December 22 , 2021.

Just a few days ago, on February 11, 2022, it was approved for import and use by the emergency annex of the China National Medical Products Administration .

 

 

 



Summarize

In the end, we must completely defeat the COVID-19, not only to establish a strong immune barrier in the population, but also to have the ability to inhibit the replication of the virus in the body.

Due to the emergence of mRNA technology, major breakthroughs have been made in vaccine development speed and capacity expansion, and mRNA vaccines against mutant strains have been rapidly developed in a short period of time.

It can be seen from the research and development process of new coronavirus antiviral drugs summarized above that the research and development of neutralizing antibodies, especially small molecule drugs, is not something that can be done overnight.

It requires a long period of technical accumulation and research and development background. Only established pharmaceutical companies have the opportunity to compete and conquer.

To truly solve the threat posed to us by the new coronavirus, we must develop broad-spectrum and efficient antiviral drugs.

This road is not easy to take, and there are many difficulties. It requires the R&D team to truly endure loneliness and be willing to spend time to study, rather than blindly Grab the hot spot.

 

 

 

 

references:

1.Monoclonal antibodies for COVID-19 therapy and SARS-CoV-2 detection

2.Current status of therapeutic monoclonal antibodies against SARS-CoV-2

3. COVID-19 vaccine, neutralizing antibody, and small molecule oral drug are effective combinations for anti-epidemic, Southwest Securities Research Center

4.Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis

5.A dual mechanism of action of AT-527 against SARS-CoV-2 polymerase

6.https://zh.wikipedia.org/wiki/PF-07321332

7.Remdesivir, Molnupiravir and Nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern

Types and mechanisms of action of new coronavirus antiviral drugs

(source:internet, reference only)


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