DISCOVERY OF A DRUG LEAD EMPLOYING A PEPTIDE LIBRARY - INHIBITION OF HIV-1 TAT AND VIRAL REPLICATION BY THE TRIPEPTIDE YPG-NH2

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