POTENCY COMPARISON OF PEPTIDOMIMETIC INHIBITORS AGAINST HIV-1 AND HIV-2 PROTEINASES - DESIGN OF EQUIPOTENT LEAD COMPOUNDS

HIV-1 and HIV-2 proteinases (PR) are responsible for the processing of viral polyproteins, a step that is crucial for the formation of infec tious virus particles. PR represents one of the most important targets for antiviral chemotherapy. Inhibitors of HIV-1 PR usually exhibit a 10- to 100-fold weaker affinity for HIV-2 PR. In order to design subna nomolar inhibitors for both HIV-1 and HIV-2 PRs, we prepared a series of compounds varying in the type of scissile bond replacement as well as in the P1, P1', and P2' side chains. While inhibitors containing re duced amide, hydroxyethylamine and statine isosteres had K-i values in the range of 10(-10)-10(-9) M against HIV-1 PR; their activities agai nst HIV-2 PR were several orders of magnitude lower. Glutamic acid was identified to be the optimal P2' residue for both PRs. HIV-2 PR was s hown to be more sensitive to P2' Glu-->Gln replacement. Using this dat a set we were able to design and prepare hydroxyethylene isostere cont aining inhibitors that were equipotent against both PRs. (C) 1997 Acad emic Press.