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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Role of Triple Hyp→Pro Substitution on Conformation andBioactivity of Integramide AMarta De Zotti 1 , Wim De Borggraeve 2 , Bernard Kaptein 3 ,Quirinus B. Broxterman 3 , Sheo B. Singh 4 , Peter J. Felock 5 ,Daria J. Hazuda 5 , Fernando Formaggio 1 , and Claudio Toniolo 11 ICB, Padova Unit, CNR, Department of Chemistry, University of Padova, Padova, 35131,Italy; 2 Department of Chemistry, Catholic University Leuven, Leuven, 3001, Belgium;3 DSM Innovative Synthesis BV, Geleen, 6160 MD, The Netherlands; 4 Medicinal Chemistry,Merck Research Laboratories, West Point, 19486, PA, U.S.A.; 5 Medicinal Chemistry,Merck Research Laboratories, Rahway, 07065, NJ, U.S.A.IntroductionAIDS is produced by HIV-induced infections. HIV integrase is an important enzyme as it iscritical for the integration of HIV genome into that of the host cell. Because this complexprocess is exclusively brought about by the virus, the enzyme, not found in the host cell,represents a safe target for the development of a single or a combined anti-HIV therapy.Integramide A is a 16-mer long, effective peptaib inhibitor of HIV-1 integrase. Its primarystructure is: Ac-D-Iva-L-Hyp-L-Iva-L-Leu-Aib-Aib-Aib-L-Hyp-L-Iva-D-Iva-Gly-OH (Ac,acetyl; Aib, α-aminoisobutyric acid; Hyp, (4R)-hydroxyproline; Iva, isovaline) [1].Results and DiscussionWe have recently described a versatile synthetic strategy in solution to afford this naturalcompound and its diastereomer at positions 14 and 15, and found that both peptides displaya significant inhibitory activity [2]. In this study, we present our data on the synthesis insolution, in-depth FT-IR absorption, CD and 2D-NMR conformational analysis (Figure 1),and biological activity against HIV-integrase (Table 1) of the analogues of the two abovementioned peptides in which all of the three (2S,4R)-Hyp residues at positions 2, 9, and 13are replaced by L-Pro.IIIFig. 1. (I) Superposition of the 22 lowest-energy backbone, mixed α-/3 10 - helical 3Dstructures(energy < 129 Kcal/mol) for the integramide A analogue containing the -L-Iva 14 -D-Iva 15 - sequence consistent with the 2D-NMR derived distances and dihedral anglerestraints. (II) Ribbon representation of the lowest-energy 3D-structure obtained for thesame peptide. The three L-Pro residues are labeled.292