Work

A synergy of activity, stability, and inhibitor‐interaction of HIV ‐1 protease mutants evolved under drug‐pressure

Year: 2020

Type: article

Abstract: A clinically‐relevant, drug‐resistant mutant of HIV‐1 protease (PR), termed Flap+ (I54V) and containing L10I, G48V, I54V and V82A mutations, is known to produce significant changes in the entropy and enthalpy balance of drug‐PR interactions, compared to wild‐type PR. A similar mutant, Flap+ (I54A) , which evolves from Flap+ (I54V) and contains the single change at residue 54 relative to Flap+ (I54V) , does not. Yet, how Flap+ (I54A) behaves in solution is not known. To understand the molecular basis of V54A evolution, we compared nuclear magnetic resonance (NMR) spectroscopy, fluorescence spectroscopy, isothermal titration calorimetry, and enzymatic assay data from four PR proteins: PR (pWT), Flap+ (I54V) , Flap+ (I54A) , and Flap+ (I54) , a control mutant that contains only L10I, G48V and V82A mutations. Our data consistently show that selection to the smaller side chain at residue 54, not only decreases inhibitor affinity, but also restores the catalytic activity.

Source: Protein Science

DOI: 10.1002/pro.4013

Authors: Shahid N. Khan, John D. Persons, Michel Guerrero, Tatiana V. Ilina, Masayuki Oda, Rieko Ishima

Institutions: Kyoto Prefectural University, University of Pittsburgh

Language: English

Topic: HIV/AIDS drug development and treatment

Subfield: Infectious Diseases

Field: Medicine

Domain: Health Sciences

Open Access status: bronze

Funders: University of Pittsburgh, National Institutes of Health, National Institute of General Medical Sciences

Awards: A low volume isothermal titration calorimeter for structure-function studies of biological macromolecules, Integration of Evolution to Avoid Resistance in Structure Based Drug Design, The Interdependency of Drug Resistance Evolution and Drug Design: HIV-1 Protease