Structural Analysis of Potent Hybrid HIV-1 Protease Inhibitors Containing Bis-tetrahydrofuran in a Pseudosymmetric Dipeptide Isostere

J Med Chem. 2020 Aug 13;63(15):8296-8313. doi: 10.1021/acs.jmedchem.0c00529. Epub 2020 Aug 3.

Abstract

The design, synthesis, and X-ray structural analysis of hybrid HIV-1 protease inhibitors (PIs) containing bis-tetrahydrofuran (bis-THF) in a pseudo-C2-symmetric dipeptide isostere are described. A series of PIs were synthesized by incorporating bis-THF of darunavir on either side of the Phe-Phe isostere of lopinavir in combination with hydrophobic amino acids on the opposite P2/P2' position. Structure-activity relationship studies indicated that the bis-THF moiety can be attached at either the P2 or P2' position without significantly affecting potency. However, the group on the opposite P2/P2' position had a dramatic effect on potency depending on the size and shape of the side chain. Cocrystal structures of inhibitors with wild-type HIV-1 protease revealed that the bis-THF moiety retained similar interactions as observed in the darunavir-protease complex regardless of the position on the Phe-Phe isostere. Analyses of cocrystal structures and molecular dynamics simulations provide insights into optimizing HIV-1 PIs containing bis-THF in non-sulfonamide dipeptide isosteres.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Crystallography, X-Ray
  • Darunavir / analogs & derivatives
  • Darunavir / pharmacology
  • Dipeptides / chemistry
  • Dipeptides / pharmacology
  • Drug Design
  • Furans / chemistry*
  • Furans / pharmacology*
  • HEK293 Cells
  • HIV Infections / drug therapy
  • HIV Infections / virology
  • HIV Protease / chemistry
  • HIV Protease / metabolism*
  • HIV Protease Inhibitors / chemistry*
  • HIV Protease Inhibitors / pharmacology*
  • HIV-1 / drug effects
  • HIV-1 / enzymology*
  • Humans
  • Models, Molecular
  • Structure-Activity Relationship

Substances

  • Dipeptides
  • Furans
  • HIV Protease Inhibitors
  • tetrahydrofuran
  • HIV Protease
  • p16 protease, Human immunodeficiency virus 1
  • Darunavir