Privileged Structures Meet Human T-Cell Leukemia Virus-1 (HTLV-1): C2-Symmetric 3,4-Disubstituted Pyrrolidines as Nonpeptidic HTLV-1 Protease Inhibitors.

Abstract

3,4-disubstituted pyrrolidines originally designed to inhibit the closely related HIV-1 protease were evaluated as privileged structures against HTLV-1 protease (HTLV-1 PR). The most potent inhibitor of this series exhibits two-digit nanomolar affinity and represents, to the best of our knowledge, the most potent nonpeptidic inhibitor of HTLV-1 PR described so far. The X-ray structures of two representatives bound to HTLV-1 PR were determined, and the structural basis of their affinity is discussed.

• Authors: Maren Kuhnert, Andreas Blum, Holger Steuber, Wibke E Diederich
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 58 Issue 11 Pg. 4845-50 (Jun 11 2015) ISSN: 1520-4804 [Electronic] United States
• PMID: 26000468 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protease Inhibitors
• Pyrrolidines
• Aspartic Acid Endopeptidases
• HTLV-1 protease

Topics

• Aspartic Acid Endopeptidases (chemistry, metabolism)
• HIV-1 (drug effects, enzymology)
• Human T-lymphotropic virus 1 (drug effects, enzymology)
• Humans
• Models, Molecular
• Molecular Structure
• Protease Inhibitors (chemistry, pharmacology)
• Protein Conformation
• Pyrrolidines (chemistry, pharmacology)
• Structure-Activity Relationship