**: Yakudu
Words: Balabala
SARS-CoV-2 is the causative agent responsible for the COVID-19 pandemic, carrying a nearly 30 kb RNA genome encoding four structural proteins (spike, envelope, membrane, and nucleocapsid), two overlapping polyproteins (PP1A and PP1AB), and several cofactors. These two polyproteins are automatically hydrolyzed into 16 non-structural proteins (NSP1-NSP16) by two viral cysteine proteases, the main protease (MPro, also known as 3-chymotrypsin-like protease, 3ClPro) and papain-like protease (PLPRO), which are required for viral replication and transcription.
The main purpose of antiviral drugs is to block the infection and spread of the virus by inhibiting or interfering with its infection or replication process for the different stages mentioned aboveDirect anti-SARS-CoV-2 drugs targeting viral proteins, as wellIndirect anti-SARS-CoV-2 drugs targeting host cell proteins
In recent years, the research and development of direct anti-SARS-CoV-2 drugs targeting viral proteins has emerged one after another, from the MPRO inhibitor Paxlovid to the MPro degrader HP211206, and the research and development of novel coronavirus drugs is facing new opportunities and challenges.
About SARS-CoV-2
Corona virus disease 2019 (COVID-19) is caused by a new single-stranded RNA coronavirus named Severe Acute Respiratory Syndrome Coron**irus 2 (SARS-CoV-2). SARS-CoV-2 is an enveloped, positive-stranded single-stranded RNA virus similar to severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and Middle East respiratory syndrome coronavirus (MERS-CoV).
The process of coronavirus entering the host cell relies on the binding of the spike protein to the angiotensin-converting enzyme 2 (ACE2) receptor on the surface of the host cell, and then enters the cell through receptor-guided endocytosis, releases the viral genome, completes the transcription of viral polymerase, carries out genome replication and structural protein synthesis, and finally assembles into complete viral particles, which are released extracellular through exocytosis to complete proliferation. After the genome enters the host cell, it encodes non-structural proteins with the help of host cell mechanisms, such as 3C-like chymotrypsin (3ClPro), papain-li ke protease (PlPro, NSP3), helicase, and RNA-dependent RNA polymerase polymerase (RDRP) and structural proteins, such as spike protein and accessory protein, for viral replication (Figure 1).
Potential targets and ** drugs
The mechanism of SARS-CoV-2 infection of host cells is proliferation through a series of processes such as virus attachment, fusion, penetration, uncoating, transcription, translation and virion release. Therefore, according to the different drug targets, antiviral drugs can be divided into direct anti-SARS-CoV-2 drugs targeting viral proteins such as spike protein, 3clpro, plpro and RDRP, and indirect anti-SARS-CoV-2 drugs targeting ACE2 and TMPPSS2 host cell proteins.
At this stage, breakthroughs have been made in oral small molecule drugs against SARS-CoV-2, and a variety of first-class drugs have entered phase clinical trials. Gilead's remdesivir and Pfizer's paxlovid (Figure 1) are the first marketed inhibitors of RDRP and 3ClPro, respectively.
Figure 1SARS-CoV-2 life cycle and effective inhibitory targets.
mPro: a potential target for COVID-19**
MPro is the main protease produced by the novel coronavirus (2019-ncov, SARS-CoV-2), and most of the functional proteins (non-structural proteins) of the coronavirus are encoded by the ORF1AB gene, which is first translated into a polyproteosome (7096AA), and then cleaved by MPro into multiple active proteins such as the viral replication protein RDRP.
In addition, this protein may cleave the intracellular protein Nemo (NF-B essential modulator, also known as IKK), thereby inhibiting the activation of the interferon signaling pathway. Therefore, antagonistic MPro can effectively inhibit viral infection and replication. Therefore, MPro is a key target for antiviral drug development. At present, the drug development research targeting SARS-CoV-2 MPro is mainly by inhibiting the activity of MPro, thereby preventing the formation of non-structural proteins of polyproteins, and ultimately inhibiting the replication of SARS-CoV-2.
Currently,already on the marketMPro inhibitorsThere is Paxlovid, which was developed by Pfizer. Paxlovid is a combination formulation of the MPRO inhibitor PF-07321332 and a low-dose riton**ir (ritonavir) (Figure 2). PF-07321332 is designed to stop the reproduction of the new coronavirus, while Riton**IR slows the breakdown of PF-07321332 in the body to keep it active in the body for a longer period of time and higher concentrations, helping to fight the virus.
With Pfizer's"Endorsements"Since then, MPRO has become the hottest target of anti-COVID oral drugs, and research on MPRO has emerged in an endless stream, and the research and development of novel coronavirus drugs for MPRO is facing new opportunities and challenges.
Figure 2PF-07321332 (left) and Riton**IR (right) structure.
Targeted protein degradation technology
Targeted protein degradation has recently emerged as a new pharmacological mechanism for alternative inhibitorsIt has potential advantages over traditional occupancy-driven pharmacology. Targeted degradation of proteins can be achieved by the development of targeted protein degradation chimeras (PROTAC) molecules. PROTAC (Figure 3) is a bifunctional molecule that targets the target protein at one end and recruits an E3 ubiquitin ligase at the other end, causing the target protein to be ubiquitinated and ultimately degraded via the ubiquitin-protease pathway. This principle has been successfully applied to multiple target targets, including kinases (RIPK2, BTK, BCR-ABL, CDK9) and transcriptases (BRD4, BRD9, TRIM24), as well as many other proteins, and has been widely deployed as an important new drug discovery strategy by major pharmaceutical companies such as Novartis, AbbVie, and Gilead.
Figure 3Protac mechanism of action.
Due to the similar challenges of target specificity and resistance in both cancer and antiviral drug discovery, targeted protein degradation may be beneficial for the development of new antiviral drugs. Because its mechanism of action is event-driven, proteasomal degradation is kinetically irreversible, allowing the degradation of multiple target molecules at low doses of protac molecules. ProTACs work in a manner that has been shown to improve target selectivity, high efficiency, and lower off-target effects compared to traditional small molecule inhibitors.
As a result, PROTAC molecules may exhibit different properties relative to conventional inhibitors and may therefore be particularly effective in targeting multifunctional viral targets. In addition, targeted protein degradation may degrade many "undruggable" viral proteins, or viral proteins of unknown function. Therefore, targeted protein degradation technology may provide a new solution for the development of drugs against SARS-CoV-2 virus.
The first MPro degrader HP211206
A possible alternative to the reversible inhibition of MPro function by the above small molecules is to degrade and remove MPro through the protein degradation mechanism of the ubiquitin proteasome system. This may be achieved through proteolysis (protacs) targeting chimeras, a strategy that has been shown to degrade proteins associated with viruses such as hepatitis and influenza. However, it has not been used for protein degradation of SARS-CoV-2.
Recently, the Faculty of Medicine of the University of Chinese and Hong Kong reported on the design, synthesis and biological properties of a new heterobifunctional small molecule. The researchers designed and synthesized the heterobifunctional molecule HP211206 as a small molecule degrader of the SARS-CoV-2 viral protein. This molecule can effectively degrade SARS-CoV-2 mPro and its drug-resistant mutants in HEK 293T cells, thereby demonstrating its potential value as an anti-SARS-CoV-2 drug (Fig. 4). This study demonstrates a chemical strategy for an important protein that plays an intervening role in the COVID-19 pandemic.
Figure 4HP211206 chemically induced degradation of SARS-CoV-2 mPro by the ubiquitin proteasome system
So far, the research and development of new coronavirus pneumonia drugs is still in full swing, and targeted protein degradation technology has brought new challenges and opportunities to it. We have reason to believe that there will be more new breakthroughs on SARS-CoV-2 targets in the future.
References:
1]de wit e, van doremalen n, falzarano d, munster vj. sars and mers: recent insights into emerging coron**iruses. nat rev microbiol. 2016 aug;14(8):523-34. doi: 10.1038/nrmicro.2016.81.
2]tan b, joyce r, tan h, hu y, wang j. sars-cov-2 main protease drug design, assay development, and drug resistance studies. acc chem res. 2023 jan 17;56(2):157-168. doi: 10.1021/acs.accounts.2c00735.
3] cromm pm, crews cm. targeted protein degradation: from chemical biology to drug discovery. cell chem biol. 2017 sep 21;24(9):1181-1190. doi: 10.1016/j.chembiol.2017.05.024.
4] sang x, wang j, zhou j, xu y, an j, warshel a, huang z. a chemical strategy for the degradation of the main protease of sars-cov-2 in cells. j am chem soc. 2023 dec 20;145(50):27248-27253. doi: 10.1021/jacs.3c12678
*Disclaimer: This article is only to introduce the research progress in the field of pharmaceutical diseases or briefly describe the research overview or share relevant information about medicine, and is not and will not make a recommendation of ** or diagnostic solutions, nor does it constitute any recommendation for related investment. If there is any omission in the content, please contact and point it out!