AEGiS-11IAC: The molecular basis of HIV-1 protease drug resistance.

11th International AIDS Conference

Vancouver, British Columbia — July 7-12, 1996

The molecular basis of HIV-1 protease drug resistance.

Int Conf AIDS 1996 Jul 7-12; 11:213 (abstract no. Th.A.154)
Ala P, Huston E, DeLoskey R, Duke J, Korant B, Chang C-H; The DuPont Merck Pharmaceutical Co., Wilmington, DE, USA. Fax: 302-695-8667.

OBJECTIVE: To identify the structural features of HIV-1 protease mutants that confer drug resistance, and utilize this information to improve drug efficacy.

METHODS: The three dimensional structures of native and several mutant HIV-1 proteases complexed with cyclic urea inhibitors, DMP323 and DMP450, have been crystallographically refined using XPLOR.

RESULTS: Native and mutant HIV-1 proteases (V82I, V82F, I84V and V82F/I84V) cocrystallized with DMP323 and DMP450 in the hexagonal space group P61 (a=b=63.3 A, c=83.8 A). The structures indicate that a loss of favorable hydrophobic interactions between mutant proteases and inhibitors is responsible for the reduced binding affinities for inhibitors. Discussion and

CONCLUSIONS: Resistant viruses have emerged in patients being treated with protease inhibitors. These viruses possess proteases that have mutations in several regions of the protein, most importantly in the substrate binding pocket and the flaps. We believe that all protease inhibitors will, to some degree, select for viruses which possess mutant proteases that will efficiently process polyprotein precursors but exhibit reduced affinities for inhibitors. Therefore, a detailed understanding of the structural changes that occur due to mutations, within the protease sequence, will be essential when designing new compounds to combat native and mutant HIV-1 proteases in future treatments.

Keywords: AEGIS, HIV Protease, HIV Protease Inhibitors, Drug Resistance, Urea, Drug Resistance, Microbial, Mutation, Human, genetics, ICA11

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