9sdm
Crystal structure of SARS-CoV-2 main protease (MPro) in complex with the covalently bound inhibitor GUE-4303 (compound 12 in publication)
Structural highlights
FunctionR1A_SARS2 Multifunctional protein involved in the transcription and replication of viral RNAs. Contains the proteinases responsible for the cleavages of the polyprotein.[UniProtKB:P0C6X7] Inhibits host translation by interacting with the 40S ribosomal subunit. The nsp1-40S ribosome complex further induces an endonucleolytic cleavage near the 5'UTR of host mRNAs, targeting them for degradation. Viral mRNAs are not susceptible to nsp1-mediated endonucleolytic RNA cleavage thanks to the presence of a 5'-end leader sequence and are therefore protected from degradation. By suppressing host gene expression, nsp1 facilitates efficient viral gene expression in infected cells and evasion from host immune response.[UniProtKB:P0C6X7] May play a role in the modulation of host cell survival signaling pathway by interacting with host PHB and PHB2. Indeed, these two proteins play a role in maintaining the functional integrity of the mitochondria and protecting cells from various stresses.[UniProtKB:P0C6X7] Responsible for the cleavages located at the N-terminus of the replicase polyprotein. In addition, PL-PRO possesses a deubiquitinating/deISGylating activity and processes both 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains from cellular substrates. Participates together with nsp4 in the assembly of virally-induced cytoplasmic double-membrane vesicles necessary for viral replication. Antagonizes innate immune induction of type I interferon by blocking the phosphorylation, dimerization and subsequent nuclear translocation of host IRF3. Prevents also host NF-kappa-B signaling.[UniProtKB:P0C6X7] Participates in the assembly of virally-induced cytoplasmic double-membrane vesicles necessary for viral replication.[UniProtKB:P0C6X7] Cleaves the C-terminus of replicase polyprotein at 11 sites. Recognizes substrates containing the core sequence [ILMVF]-Q-|-[SGACN]. Also able to bind an ADP-ribose-1-phosphate (ADRP).[UniProtKB:P0C6X7] Plays a role in the initial induction of autophagosomes from host reticulum endoplasmic. Later, limits the expansion of these phagosomes that are no longer able to deliver viral components to lysosomes.[UniProtKB:P0C6X7] Forms a hexadecamer with nsp8 (8 subunits of each) that may participate in viral replication by acting as a primase. Alternatively, may synthesize substantially longer products than oligonucleotide primers.[UniProtKB:P0C6X7] Forms a hexadecamer with nsp7 (8 subunits of each) that may participate in viral replication by acting as a primase. Alternatively, may synthesize substantially longer products than oligonucleotide primers.[UniProtKB:P0C6X7] May participate in viral replication by acting as a ssRNA-binding protein.[UniProtKB:P0C6X7] Plays a pivotal role in viral transcription by stimulating both nsp14 3'-5' exoribonuclease and nsp16 2'-O-methyltransferase activities. Therefore plays an essential role in viral mRNAs cap methylation.[UniProtKB:P0C6X7] Publication Abstract from PubMedThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causative agent of the coronavirus disease 2019 (COVID-19), is still circulating and posing a health threat to the global population. Its main protease (M(pro)) constitutes an excellent target for the development of antivirals due to its indispensable role in the viral replication cycle. In this work, we employed a sequential approach to identify a potent azapeptide-based M(pro) inhibitor. Starting from a series of small-molecule peptidomimetics, identical in their scaffold but equipped with different cysteine-reactive groups, we identified auspicious warheads. The combination of selected moieties with an optimized, previously described P1-P4 azapeptide structure resulted in a potent M(pro) inactivator (12) with a k(inac)/K(i) value of 78,900 M(-1)s(-1). The chloracetohydrazide derivative 12 exhibited antiviral activity (EC(50) = 0.47 microM), no cytotoxicity, and plasma stability. The molecular interaction of 12 with M(pro) was elucidated by an X-ray crystal structure. A thioether linkage was generated through a nucleophilic substitution of chloride by the active-site thiolate, giving rise to irreversible inhibition. Sequential Optimization Approach Toward an Azapeptide-Based SARS-CoV-2 Main Protease Inhibitor.,Voget R, Steiger V, Breidenbach J, Sylvester K, Muller-Ruttloff C, Yang CC, Ziebuhr J, Strater N, Muller CE, Gutschow M Arch Pharm (Weinheim). 2025 Dec;358(12):e70175. doi: 10.1002/ardp.70175. PMID:41431928[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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