Lack of synergy for inhibitors targeting a multi-drug-resistant HIV-1 protease
Authors
King, Nancy M.Melnick, Laurence
Prabu-Jeyabalan, Moses
Nalivaika, Ellen A.
Yang, Shiow-Shong
Gao, Yun
Nie, Xiaoyi
Zepp, Charles
Heefner, Donald L.
Schiffer, Celia A.
UMass Chan Affiliations
Department of Biochemistry and Molecular PharmacologyDocument Type
Journal ArticlePublication Date
2002-01-16Keywords
Anti-HIV AgentsBinding Sites
Crystallography, X-Ray
Drug Delivery Systems
Drug Resistance, Multiple
Drug Synergism
HIV Protease
HIV Protease Inhibitors
HIV-1
Humans
Indinavir
Mutation
Protein Conformation
Structure-Activity Relationship
Thermodynamics
Biochemistry, Biophysics, and Structural Biology
Life Sciences
Medicine and Health Sciences
Microbiology
Metadata
Show full item recordAbstract
The three-dimensional structures of indinavir and three newly synthesized indinavir analogs in complex with a multi-drug-resistant variant (L63P, V82T, I84V) of HIV-1 protease were determined to approximately 2.2 A resolution. Two of the three analogs have only a single modification of indinavir, and their binding affinities to the variant HIV-1 protease are enhanced over that of indinavir. However, when both modifications were combined into a single compound, the binding affinity to the protease variant was reduced. On close examination, the structural rearrangements in the protease that occur in the tightest binding inhibitor complex are mutually exclusive with the structural rearrangements seen in the second tightest inhibitor complex. This occurs as adaptations in the S1 pocket of one monomer propagate through the dimer and affect the conformation of the S1 loop near P81 of the other monomer. Therefore, structural rearrangements that occur within the protease when it binds to an inhibitor with a single modification must be accounted for in the design of inhibitors with multiple modifications. This consideration is necessary to develop inhibitors that bind sufficiently tightly to drug-resistant variants of HIV-1 protease to potentially become the next generation of therapeutic agents.Source
Protein Sci. 2002 Feb;11(2):418-29. Link to article on publisher's websiteDOI
10.1110/ps.25502Permanent Link to this Item
http://hdl.handle.net/20.500.14038/39022PubMed ID
11790852Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1110/ps.25502