AAC Accepts, published online ahead of print on 1 October 2007

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Antimicrob. Agents Chemother. doi:10.1128/AAC.00905-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

IN VITRO RESISTANCE STUDIES OF RUPINTRIVIR, A NOVEL INHIBITOR OF HUMAN RHINOVIRUS 3C PROTEASE

S. L. BINFORD, P. T. WEADY, F. MALDONADO, M. A. BROTHERS, D. A. MATTHEWS, and A. K. PATICK^*

Pfizer Global Research and Development, San Diego, CA, 92121

^* To whom correspondence should be addressed. Email: amy.patick{at}pfizer.com.

Rupintrivir (formerly AG7088) is an irreversible inhibitor of human rhinovirus (HRV) 3C protease that has demonstrated in vitro antiviral activity against all HRVs tested consistent with its interaction with a strictly conserved subset of amino acids in 3C protease. The potential for resistance was studied following in vitro serial passage of HRV 14, 2, 39, and Hanks in the presence of increasing rupintrivir concentrations. HRV variants with reduced susceptibility to rupintrivir (7-fold for HRV 14) or with no significant reductions in susceptibility but genotypic changes (HRV 2, 39 and Hanks) were initially isolated following 14 to 40 cumulative days in culture (3 to 6 passages). Sequence analysis of 3C protease identified one to three substitutions in diverse patterns but with common features (T129T/A, T131T/A, T143P/S in HRV 14; N165T in HRV 2; N130N/K, L136L/F in HRV 39; T130A in HRV Hanks). Notably, 3 of 4 HRV variants contained a substitution at residue 130 (129 in HRV 14). Continued selection in escalating concentrations of rupintrivir (40-72 days) resulted in accumulation of additional mutations (A121A/V, Y139Y/H in HRV 14; E3E/G and A103A/V in HRV 2; S105T in HRV 39) with only minimal further reductions in susceptibility (up to 5-fold). The ability of specific substitutions to confer resistance was examined by susceptibility testing of HRV 14 variants constructed to contain 3C protease mutations. In summary, the slow accumulation of multiple amino acid substitutions with only minimal to moderate reductions in susceptibility highlight the advantages of 3C protease as an antiviral target.

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