Application of ring-closing metathesis macrocyclization to the development of Tsg101-binding antagonists.

Abstract

HIV-1 viral budding involves binding of the viral Gag(p6) protein to the ubiquitin E2 variant domain of the human tumor susceptibility gene 101 protein (Tsg101). Recognition of p6 by Tsg101 is mediated in part by a proline-rich motif that contains the sequence 'Pro-Thr-Ala-Pro' ('PTAP'). Using the p6-derived 9-mer sequence 'PEPTAPPEE', we had previously improved peptide binding affinity by employing N-alkylglycine ('peptoid') residues. The current study applies ring-closing metathesis macrocyclization strategies to Tsg101-binding peptide-peptoid hybrids as an approach to stabilize binding conformations and to observe the effects of such macrocyclization on Tsg101-binding affinity and bioavailability.