title: A novel constrained reduced-amide inhibitor of HIV-1 protease derived from the sequential incorporation of gamma-turn mimetics into a model substrate.
abstract: C7 mimetics, designed to lock three amino acid residues of a peptide chain into a gamma-turn conformation, were introduced sequentially between the P3 to P2' positions of a model HIV-1 protease substrate I (resulting in compounds II-IV) to probe its conformational requirements in binding to HIV-1 protease. Of these, compound IIIa with the C7 mimetic replacing Asn-Tyr-Pro, corresponding to the P2 through P1' positions of substrate, was found to be an inhibitor with a Ki of 147 microM. Reduction of the amide bond in the C7 mimetic of IIIa resulted in a novel constrained reduced-amide mimetic VIa with a Ki of 430 nM. This corresponds to over a 300-fold improvement in inhibitory activity over the original C7 mimetic. The inhibitory activity of mimetic VIa was in addition found to be 44-fold better than a similar linear reduced-amide containing inhibitor V. The synthesis of these mimetics are described.
authors.affiliation: Department of Medicinal Chemistry, Peptidomimetic Research, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406.
authors.forename: K A
authors.initials: KA
authors.lastname: Newlander
authors.forename: J F
authors.initials: JF
authors.lastname: Callahan
authors.forename: M L
authors.initials: ML
authors.lastname: Moore
authors.forename: T A
authors.initials: TA
authors.lastname: Tomaszek
authors.forename: W F
authors.initials: WF
authors.lastname: Huffman
mesh_terms: D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013566:Sympathomimetics / Q000138:chemical synthesis* / Q000378:metabolism
chemical_list: D017320:HIV Protease Inhibitors; D013566:Sympathomimetics