The discovery of allyltyrosine based tripeptides as selective inhibitors of the HIV-1 integrase strand-transfer reaction

Authors

Neal Dalton, University of WollongongFollow
Christopher P. Gordon, University of WollongongFollow
Timothy Boyle, University of Wollongong
Nicholas Vandegraaff, Avexa Ltd
John Deadman, Avexa Ltd
David I. Rhodes, Avexa LtdFollow
Jonathon A. Coates, Avexa Ltd
Stephen G. Pyne, University of WollongongFollow
Paul A. Keller, University of WollongongFollow
John B. Bremner, University of WollongongFollow

RIS ID

112992

Publication Details

Dalton, N., Gordon, C. P., Boyle, T. P., Vandegraaff, N., Deadman, J., Rhodes, D. I., Coates, J. A., Pyne, S. G., Keller, P. A. & Bremner, J. B. (2016). The discovery of allyltyrosine based tripeptides as selective inhibitors of the HIV-1 integrase strand-transfer reaction. Organic and Biomolecular Chemistry, 14 (25), 6010-6023.

Abstract

From library screening of synthetic antimicrobial peptides, an O-allyltyrosine-based tripeptide was identified to possess inhibitory activity against HIV-1 integrase (IN) exhibiting an IC₅₀ value of 17.5 μM in a combination 3′-processing and strand transfer microtitre plate assay. The tripeptide was subjected to structure-activity relationship (SAR) studies with 28 peptides, incorporating an array of natural and non-natural amino acids. Resulting SAR analysis revealed the allyltyrosine residue was a key feature for IN inhibitory activity whilst incorporation of a lysine residue and extended hydrophilic chains bearing a terminal methyl ester was advantageous. Addition of hydrophobic aromatic moieties to the N-terminal of the scaffold afforded compounds with improved inhibitory activity. Consolidation of these functionalities lead to the development of the tripeptide 96 which specifically inhibited the IN strand-transfer reaction with an IC₅₀ value of 2.5 μM.