The nontoxic tripeptide glycyl-prolyl-glycine amide inhibits the replication of human immunodeficiency virus type 1

Objective: To determine whether short peptides corresponding to the RGPGR m otif of the V3 loop of gp120 have antihuman immunodeficiency virus type 1 ( anti-HIV-1) activity. Design/Methods: Short peptides were tested against the HIV-1 laboratory str ains and clinical isolates. Results: The tripeptide glycl-prolyl-glycine amide (GPG-NH2) inhibited the replication of both laboratory strains and 47 clinical isolates, including 19 strains that were resistant to other drugs or that were from patients wi th failing therapy. The 50% inhibitory; concentrations values were 2.7 to 3 7 muM. Phenotypic change of two isolates from nonsyncytia-inducing to syncy tia-inducing did not change their sensitivity to GPG-NH2. The tripeptide ad ded to the antiviral effect of both zidovudine and ritonavir. Conclusions: The tripeptide GPG-NH2 is a nontoxic compound that inhibits th e replication of HIV-1 by an apparently new mode of action. Glycyl-propyl-g lycine-NH2 might prove useful by itself or as a lead compound for the treat ment of drug-resistant HIV-1. Glycyl-prolyl-glycine-NH2 is currently underg oing phase I/II human clinical trials in Sweden.