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Research article - Peer-reviewed, 2014

Identification of Weak Points of Hepatitis C Virus NS3 Protease Inhibitors Using Surface Plasmon Resonance Biosensor-Based Interaction Kinetic Analysis and Genetic Variants

Gustafsson, Sofia Svahn; Ehrenberg, Angelica; Schmuck, Benjamin; Anwar, Muhammad Ikram; Danielson, U. Helena


To aid the design of next generation hepatitis C virus (HCV) drugs, the kinetics of the interactions between NS3 protease inhibitors and enzyme from genotypes 1a, 1b, and 3a have been characterized. The linear mechanism-based inhibitors VX-950 (telaprevir) and SCH 503034 (boceprevir) benefited from covalent adduct formation. However, the apparent affinities were rather weak (VX-950, K-D* of 340, 8.5, and 1000 nM for genotypes 1a, 1b and 3a, respectively; SCH 503034, K-D* of 90 and 3.9 nM for 1b and 3a, respectively). The non-mechanism-based macrocyclic inhibitors BILN-2016 (ciluprevir) and ITMN-191 (danoprevir) had faster association and slower dissociation kinetics, indicating that rigidification is kinetically favorable. ITMN-191 had nanomolar affinities for all genotypes (K-D* of 0.13, 1.6, and 0.52 nM), suggesting that a broad spectrum drug is conceivable. The data show that macrocyclic scaffolds and mechanism-based inhibition are advantageous but that there is considerable room for improvement of the kinetics of HCV protease targeted drugs.

Published in

Journal of Medicinal Chemistry
2014, volume: 57, number: 5, pages: 1802-1811

Authors' information

Gustafsson, Sofia Svahn
Uppsala University
Ehrenberg, Angelica
Uppsala University
Uppsala University
Anwar, Muhammad Ikram
Pakistan Institute of Engineering and Applied Science
Danielson, U. Helena
Uppsala University

UKÄ Subject classification

Pharmaceutical Sciences
Medicinal Chemistry

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