ArticleBiochemistry2017
Structural Basis for the Species-Selective Binding of N,C-Capped Dipeptides to the Mycobacterium tuberculosis Proteasome.
Article in Biochemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 15 citations in OpenAlex.
- Identification of Natural Inhibitors against theCurrent drug targets · 2026Article
- Scaffold Hopping in Tuberculosis Drug Discovery: Principles, Applications, and Case Studies.Journal of medicinal chemistry · 2025Review
- Design, Synthesis, and Optimization of Macrocyclic Peptides as Species-Selective Antimalaria Proteasome Inhibitors.Journal of medicinal chemistry · 2022Article
- Macrocyclic Peptides that Selectively Inhibit theJournal of medicinal chemistry · 2021Article
- Mechanistic and thermodynamic characterization of oxathiazolones as potent and selective covalent immunoproteasome inhibitors.Computational and structural biotechnology journal · 2021Article
- Structure-Activity Relationships of Noncovalent Immunoproteasome β5i-Selective Dipeptides.Journal of medicinal chemistry · 2020Article
- Psoralen Derivatives as Inhibitors ofMolecules (Basel, Switzerland) · 2020Article
- Proteasome, a Promising Therapeutic Target for Multiple Diseases Beyond Cancer.Drug design, development and therapy · 2020Review
- Selective Phenylimidazole-Based Inhibitors of theJournal of medicinal chemistry · 2019Article
- The proteasome as a target to combat malaria: hits and misses.Translational research : the journal of laboratory and clinical medicine · 2018Review
- Antimalarial proteasome inhibitor reveals collateral sensitivity from intersubunit interactions and fitness cost of resistance.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Targeting the Proteostasis Network for Mycobacterial Drug Discovery.ACS infectious diseases · 2018Review
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
The Mycobacterium tuberculosis (Mtb) 20S proteasome is vital for the pathogen to survive under nitrosative stress in vitro and to persist in mice. To qualify for drug development, inhibitors targeting Mtb 20S must spare both the human constitutive proteasome (c-20S) and immunoproteasome (i-20S). We recently reported members of a family of noncovalently binding dipeptide proteasome inhibitors that are highly potent and selective for Mtb 20S over human c-20S and i-20S. To understand the structural basis of their potency and selectivity, we have studied the structure-activity relationship of six derivatives and solved their cocrystal structures with Mtb 20S. The dipeptide inhibitors form an antiparallel β-strand with the active site β-strands. Selectivity is conferred by several features of Mtb 20S relative to its mouse counterparts, including a larger S1 pocket, additional hydrogen bonds in the S3 pocket, and hydrophobic interactions in the S4 pocket. Serine-20 and glutamine-22 of Mtb 20S interact with the dipeptides and confer Mtb-specific inhibition over c-20S and i-20S. The Mtb 20S and mammalian i-20S have a serine-27 that interacts strongly with the dipeptides, potentially explaining the higher inhibitory activity of the dipeptides toward i-20S over c-20S. This detailed structural knowledge will aid in optimizing the dipeptides as anti-tuberculosis drugs.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.