Discovery of a Drug Lead Employing a Peptide Library: Inhibition of HIV-1 Tat and Viral Replication by the Tripeptide YPG-NH 2

A library of the 8000 tripeptides derivable from coded amino acids was prepared in 20 sets of 400 using solid phase synthesis on a benzhydrylamine resin. The peptide mixtures, as C-terminal amides, were screened for inhibition of secreted alkaline phosphatase expression in a cellular (COS) system wherein a transfected SeAP gene construct was under control of the HIV-1 LTR promoter, activated by the product of a cotransfected HIV Tat gene construct. Thus, YPG-NH₂ was discovered as an inhibitor of HIV-1 Tat function and then shown to block HIV replication in a CD₄⁺ T-cell line (CEM) with IC₅₀ = 35μM.