Adaptive inhibitors of the HIV-1 protease

Hiroyasu Ohtaka, Ernesto I Freire

Research output: Contribution to journalArticle

Abstract

A significant obstacle to the efficacy of drugs directed against viral targets is the presence of amino acid polymorphisms in the targeted molecules. Amino acid polymorphisms may occur naturally due to the existence of variations within and between viral strains or as the result of mutations associated with drug resistance. An ideal drug will be one that is extremely effective against a primary target and maintains its effectiveness against the most important variations of the target molecule. A drug that simultaneously inhibits different variants of the target will lead to a faster suppression of the virus, retard the appearance of drug-resistant mutants and provide more efficacious and, in the long range, more affordable therapies. Drug molecules with the ability to inhibit several variants of a target with high affinity have been termed adaptive drugs (Nat. Biotechnol. 20 (2002) 15; Biochemistry 42 (2003) 8459; J. Cell. Biochem. S37 (2001) 82). Current drug design paradigms are predicated upon the lock-and-key hypothesis, which emphasizes shape complementarity as a way to attain specificity and improved binding affinity. Shape complementarity is accomplished by the introduction of conformational constraints in the drug molecule. While highly constrained molecules do well against a unique target, they lack the ability to adapt to target variations like those originating from naturally occurring polymorphisms or drug-resistant mutations. Targeting an array of closely related targets rather than a single one while still maintaining selectivity, requires a different approach. A plausible strategy for designing high affinity adaptive inhibitors is to engineer their most critical interactions (for affinity and specificity) with conserved regions of the target while allowing for adaptability through the introduction of flexible asymmetric functionalities in places facing variable regions of the target. The fundamental thermodynamics and structural principles associated with this approach are discussed in this chapter.

Original languageEnglish (US)
Pages (from-to)193-208
Number of pages16
JournalProgress in Biophysics and Molecular Biology
Volume88
Issue number2
DOIs
StatePublished - Jun 2005

Fingerprint

Pharmaceutical Preparations
Amino Acids
Mutation
Human immunodeficiency virus 1 p16 protease
Drug Design
Thermodynamics
Drug Resistance
Biochemistry
Viruses
Therapeutics

Keywords

  • Adaptive inhibitors
  • Binding enthalpy
  • Binding thermodynamics
  • Drug design
  • Drug resistance
  • Isothermal titration calorimetry

ASJC Scopus subject areas

  • Molecular Biology
  • Biophysics

Cite this

Adaptive inhibitors of the HIV-1 protease. / Ohtaka, Hiroyasu; Freire, Ernesto I.

In: Progress in Biophysics and Molecular Biology, Vol. 88, No. 2, 06.2005, p. 193-208.

Research output: Contribution to journalArticle

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