Identification of constrained peptidomimetic chemotypes as HIV protease inhibitors

• HIV-1 protease and Candida albicans Sap2 share structural similarity.
• A library of Sap2-active bicyclic peptidomimetics was assayed toward HIV protease.
• Synthesis of a pool of tripeptide mimetics to expand the library.
• Two compounds with inhibition in low micromolar range were selected.
• 4-Benzyl-peptidomimetics addressed S1′ subsite with the Phe side-chain isostere.

Small-molecule peptidomimetic inhibitors that already showed activity towards Secreted aspartic protease 2 as anti-Candida agents are herein presented as candidate HIV protease inhibitors. A library of 6,8-dioxa-3-azabicyclo[3.2.1]-octane peptidomimetic scaffolds was screened towards HIV protease, resulting in the identification of hit compounds possessing IC50 in the sub-micromolar range, and showing the bicyclic acetal portion as a potential transition state analogue in the interaction with catalytic aspartic acid residues.

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