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| Clinical data | |
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| Other names | HY-157403, CS-0915641, XB5 |
| Routes of administration | By mouth |
| Identifiers | |
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| PubChem CID | |
| Chemical and physical data | |
| Formula | C29H36N6O2 |
| Molar mass | 500.647 g·mol−1 |
| 3D model (JSmol) | |
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Jun12682 is an experimental antiviral medication being studied as a potential treatment for COVID-19. It is believed to work by inhibiting SARS-CoV-2 papain-like protease (PLpro), a crucial enzyme for viral replication. [1] [2] [3] [4]
The SARS-CoV-2 virus utilizes several proteases to assist in creating proteins that are essential for viral replication. Among these, the papain-like protease (PLpro) is responsible for cleaving specific sites in the viral polyproteins, facilitating the production of functional viral proteins. By binding to both the BL2 groove and Val70Ub site of PLpro protease, Jun12682 is believed to interfere with the virus's ability to produce new viral proteins, thereby inhibiting the viral replication process. In a study involving mice infected with SARS-CoV-2, mice orally administered Jun12682 experienced reduced viral loads in their lungs, decreased lung lesions, reduced weight loss, and improved survival when compared to those in the control group. [1] [2] [3]
The protease targeted by Jun12682 (PLpro) is distinct from the protease targeted by some other antiviral medications, such as nirmatrelvir/ritonavir, which specifically inhibit the SARS-CoV-2 main protease (Mpro). Laboratory studies have indicated that Jun12682 may retain efficacy against certain strains of SARS-CoV-2 that have developed resistance to other antiviral agents, including nirmatrelvir. This characteristic may position Jun12682 as an option in the treatment of COVID-19 in cases where viral resistance to existing therapies is a concern. [1] [2] [3] [4]
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The 3C-like protease (3CLpro) or main protease (Mpro), formally known as C30 endopeptidase or 3-chymotrypsin-like protease, is the main protease found in coronaviruses. It cleaves the coronavirus polyprotein at eleven conserved sites. It is a cysteine protease and a member of the PA clan of proteases. It has a cysteine-histidine catalytic dyad at its active site and cleaves a Gln–(Ser/Ala/Gly) peptide bond.
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Nirmatrelvir is an antiviral medication developed by Pfizer which acts as an orally active 3C-like protease inhibitor. It is part of a nirmatrelvir/ritonavir combination used to treat COVID-19 and sold under the brand name Paxlovid.
GRL-0617 is a drug which is one of the first compounds discovered that acts as a selective small-molecule inhibitor of the protease enzyme papain-like protease (PLpro) found in some human pathogenic viruses, including the coronavirus SARS-CoV-2. It has been shown to inhibit viral replication in silico and in vitro.
The COVID Moonshot is a collaborative open-science project started in March 2020 with the goal of developing an un-patented oral antiviral drug to treat SARS-CoV-2, the virus causing COVID-19. COVID Moonshot researchers are targeting the proteins needed to form functioning new viral proteins. They are particularly interested in proteases such as 3C-like protease (Mpro), a coronavirus nonstructural protein that mediates the breaking and replication of proteins.
The nidoviral papain-like protease is a papain-like protease protein domain encoded in the genomes of nidoviruses. It is expressed as part of a large polyprotein from the ORF1a gene and has cysteine protease enzymatic activity responsible for proteolytic cleavage of some of the N-terminal viral nonstructural proteins within the polyprotein. A second protease also encoded by ORF1a, called the 3C-like protease or main protease, is responsible for the majority of further cleavages. Coronaviruses have one or two papain-like protease domains; in SARS-CoV and SARS-CoV-2, one PLPro domain is located in coronavirus nonstructural protein 3 (nsp3). Arteriviruses have two to three PLP domains. In addition to their protease activity, PLP domains function as deubiquitinating enzymes (DUBs) that can cleave the isopeptide bond found in ubiquitin chains. They are also "deISGylating" enzymes that remove the ubiquitin-like domain interferon-stimulated gene 15 (ISG15) from cellular proteins. These activities are likely responsible for antagonizing the activity of the host innate immune system. Because they are essential for viral replication, papain-like protease domains are considered drug targets for the development of antiviral drugs against human pathogens such as MERS-CoV, SARS-CoV, and SARS-CoV-2.
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