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9mdq

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Crystal Structure of SARS-CoV-2 Omicron Main Protease (Mpro) Complex with Azapeptide Inhibitor 20a

Structural highlights

9mdq is a 1 chain structure with sequence from Severe acute respiratory syndrome coronavirus 2. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.6Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

R1A_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 PubMed

M(pro) of SARS-CoV-2 plays a vital role in the replication and pathogenesis of virus. Additionally, its high conservation within the Coronaviridae family makes it an attractive therapeutic target for developing broad-spectrum agents. This study describes the design, synthesis, and structure-activity relationships of azapeptide-based SARS-CoV-2 M(pro) inhibitors, leading to several compounds with nanomolar IC(50) values. Examples include 14r (IC(50) = 13.3 nM), 14s (IC(50) = 30.6 nM), 20a (TPG-20a, IC(50) = 28.0 nM), and 20g (IC(50) = 30.4 nM). Some compounds inhibit MERS-CoV and SARS-CoV-1 M(pro) but not the human protease cathepsin L. Several inhibitors, such as 20a and 20f, exhibit antiviral activity with potencies comparable to nirmatrelvir and activity against the E166V-carrying SARS-CoV-2 variant (SARS-CoV-2(E166V)). An M(pro) cocrystal structure with 20a shows a covalent adduct with the catalytic Cys145. Overall, these new inhibitors are promising chemical tools that may contribute to the identification of future pan-anticoronaviral drugs.

Azapeptide-Based SARS-CoV-2 Main Protease Inhibitors: Design, Synthesis, Enzyme Inhibition, Structural Determination, and Antiviral Activity.,Flury P, Vishwakarma J, Sylvester K, Higashi-Kuwata N, Dabrowska AK, Delgado R, Cuell A, Basu R, Taylor AB, de Oliveira EG, Magalhaes Serafim MS, Qiao J, Chen Y, Yang S, O'Donoghue AJ, Mitsuya H, Gutschow M, Laufer SA, Muller CE, Harris RS, Pillaiyar T J Med Chem. 2025 Sep 11. doi: 10.1021/acs.jmedchem.5c01520. PMID:40932417^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Flury P, Vishwakarma J, Sylvester K, Higashi-Kuwata N, Dabrowska AK, Delgado R, Cuell A, Basu R, Taylor AB, de Oliveira EG, Magalhães Serafim MS, Qiao J, Chen Y, Yang S, O'Donoghue AJ, Mitsuya H, Gütschow M, Laufer SA, Müller CE, Harris RS, Pillaiyar T. Azapeptide-Based SARS-CoV-2 Main Protease Inhibitors: Design, Synthesis, Enzyme Inhibition, Structural Determination, and Antiviral Activity. J Med Chem. 2025 Sep 11. PMID:40932417 doi:10.1021/acs.jmedchem.5c01520