Design, Synthesis, Evaluation, and Crystallographic-Based Structural Studies of HIV-1 Protease Inhibitors with Reduced Response to the V82A Mutation

Abstract

In our quest for HIV-1 protease inhibitors that are not affected by the V82A resistance mutation, we have synthesized and tested a second generation set of C2-symmetric HIV-1 protease inhibitors that contain a cyclohexane group at P1 and/or P1'. The binding affinity results indicate that these compounds have an improved response to the appearance of the V82A mutation than the parent compound. The X-ray structure of one of these compounds with the V82A HIV-1 PR variant provides the structural rationale for the better resistance profile of these compounds. Moreover, scrutiny of the X-ray structure suggests that the ring of the Cha side chain might be in a boat rather than in the chair conformation, a result supported by molecular dynamics simulations.

Recent Progress in the Development of HIV-1 Protease Inhibitors for the Treatment of HIV/AIDS

“…This compound exhibited a K i value of 1.3 nM. 150 Incorporation of a phenylalanine-proline dihydroxyethylene isostere as the transition state mimic has also been investigated. 151 Inhibitors 95 and 96 showed good enzymatic activity with IC 50 values of <0.6 and 9.6 nM, respectively.…”

Amino Acid and Peptide‐Based Antiviral Agents

“… Protease inhibitors incorporating l ‐valine residues: PI with tertiary hydroxy group as transition state bioisostere 1 ; [11,12] PI with vicinal diol transition state bioisostere 2 ; [13] pseudosymmetrical PI with vicinal diol transition state bioisostere 3 ; [14] symmetrical PI with vicinal diol transition state bioisostere 4 ; [15] inhibitor of HIV protease dimerization 5 [16] . Transition state bioisosteres are marked in red.…”

Mining the Protein Data Bank to Differentiate Error from Structural Variation in Clustered Static Structures: An Examination of HIV Protease

“…Highly Active Anti-Retroviral Therapy (HAART) combines multiple drugs, significantly improving prognoses [6]. However, the high mutation rate of the virus has given rise to a number of polymorphs, including drug-resistant mutants [5,7,8]. This has prompted extensive study of the mechanisms of inhibitor action and resistance in the various polymorphs.…”

“…This has prompted extensive study of the mechanisms of inhibitor action and resistance in the various polymorphs. Recent investigations have looked at the structure of PR in different polymorphic forms, in both the bound and ligand-free state [8,9]. …”