Structural Basis for HTLV‑1 Protease Inhibition by the HIV‑1 Protease Inhibitor Indinavir

• Published in: Journal of medicinal chemistry Vol. 57; no. 14; pp. 6266 - 6272
• Main Authors: Kuhnert, Maren, Steuber, Holger, Diederich, Wibke E
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 24.07.2014
• Subjects: Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - chemistry; Aspartic Acid Endopeptidases - metabolism; Crystallography, X-Ray; Dose-Response Relationship, Drug; HIV Protease Inhibitors - chemistry; HIV Protease Inhibitors - pharmacology; Indinavir - chemistry; Indinavir - pharmacology; Models, Molecular; Molecular Structure; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm500402c

HTLV-1 protease (HTLV-1 PR) is an aspartic protease which represents a promising drug target for the discovery of novel anti-HTLV-1 drugs. The X-ray structure of HTLV-1 PR in complex with the well-known and approved HIV-1 PR inhibitor Indinavir was determined at 2.40 Å resolution. In this contribution, we describe the first crystal structure in complex with a nonpeptidic inhibitor that accounts for rationalizing the rather moderate affinity of Indinavir against HTLV-1 PR and provides the basis for further structure-guided optimization strategies.