ArticleInternational journal of molecular sciences2021
Structural and Biochemical Analysis of the Dual Inhibition of MG-132 against SARS-CoV-2 Main Protease (Mpro/3CLpro) and Human Cathepsin-L.
Article in International journal of molecular sciences, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 86 citations in OpenAlex.
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- Broad-acting antivirals: the pursuit of pan-viral therapeutics in the era of pandemics.Journal of virology · 2026Review
- Statistical crystallography reveals an allosteric network in SARS-CoV-2 MCommunications biology · 2026Article
- Enhancing the Outcome of Crystallographic Fragment Screening by Choosing the Optimal Protein Crystal Form.Small science · 2026Article
- Andrographolide targets syndecan4 to impair its interaction with syntenin and inhibits the biogenesis of small extracellular vesicles.The Journal of biological chemistry · 2026Article
- Targeting Glycolysis with 2-Deoxy-D-Glucose and Lysosomal Integrity with L-Leucyl-L-Leucine Methyl Ester as Antimelanoma Strategy.Pharmaceutics · 2025Article
- The novel human astrovirus VA1 requires the proteasome during cell entry.The Journal of general virology · 2025Article
- An orally available MNature communications · 2025Article
- Peptidomimetic Phenoxymethyl Ketone Warheads as Potent Dual-Mode Inhibitors against SARS-CoV-2 MJournal of medicinal chemistry · 2025Article
- Macromolecular crystallography at Elettra: current and future perspectives.Journal of synchrotron radiation · 2025Article
- Peptide Aldehydes Incorporating Thiazol-4-yl Alanine Are Potent In Vitro Inhibitors of SARS-CoV-2 Main Protease.ACS medicinal chemistry letters · 2024Article
- Advancements in the Development of Anti-SARS-CoV-2 Therapeutics.International journal of molecular sciences · 2024Review
- An automated positive selection screen in yeast provides support for boron-containing compounds as inhibitors of SARS-CoV-2 main protease.Microbiology spectrum · 2024Article
- Taming the storm: potential anti-inflammatory compounds targeting SARS-CoV-2 MPro.Inflammopharmacology · 2024Review
- Advances in the Search for SARS-CoV-2 MPathogens (Basel, Switzerland) · 2024Review
- A comprehensive study of SARS-CoV-2 main protease (Mpro) inhibitor-resistant mutants selected in a VSV-based system.PLoS pathogens · 2024Article
- Identification of Dual Inhibitors Targeting Main Protease (MACS medicinal chemistry letters · 2024Article
- Article
- Unexpected Single-Ligand Occupancy and Negative Cooperativity in the SARS-CoV-2 Main Protease.Journal of chemical information and modeling · 2024Article
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Authors and funding
11 authors at 5 institutions in 2 countries.
Funding
Abstract
After almost two years from its first evidence, the COVID-19 pandemic continues to afflict people worldwide, highlighting the need for multiple antiviral strategies. SARS-CoV-2 main protease (Mpro/3CLpro) is a recognized promising target for the development of effective drugs. Because single target inhibition might not be sufficient to block SARS-CoV-2 infection and replication, multi enzymatic-based therapies may provide a better strategy. Here we present a structural and biochemical characterization of the binding mode of MG-132 to both the main protease of SARS-CoV-2, and to the human Cathepsin-L, suggesting thus an interesting scaffold for the development of double-inhibitors. X-ray diffraction data show that MG-132 well fits into the Mpro active site, forming a covalent bond with Cys145 independently from reducing agents and crystallization conditions. Docking of MG-132 into Cathepsin-L well-matches with a covalent binding to the catalytic cysteine. Accordingly, MG-132 inhibits Cathepsin-L with nanomolar potency and reversibly inhibits Mpro with micromolar potency, but with a prolonged residency time. We compared the apo and MG-132-inhibited structures of Mpro solved in different space groups and we identified a new apo structure that features several similarities with the inhibited ones, offering interesting perspectives for future drug design and in silico efforts.
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