Anti HIV-1 virucidal activity of polyamide nucleic acid-membrane transducing peptide conjugates targeted to primer binding site of HIV-1 genome.

We have shown that polyamide nucleic acids (PNAs) targeted to the PBS (PNA(PBS)) and A-loop (PNA(A-loop)) sequences, when transfected into cells, inhibit HIV-1 replication by blocking the initiation of reverse transcription via destabilizing tRNA(3)(Lys) primer from the viral genome. Here we demonstrate that both PNA(PBS) and PNA(A-loop) conjugated with the membrane-transducing peptide (MTD) vectors penetratin and Tat are rapidly taken up by cells and inhibit HIV-1 replication. Moreover, MTD peptide conjugates of PNA(PBS) and PNA(A-loop) displayed potent virucidal activity against HIV-1. Brief exposure of HIV-1 virions to these conjugates rendered them noninfectious. The IC(50) values for virucidal activity were in the range of approximately 50 nM; IC(50) values for inhibition of HIV-1 replication/infection were 0.5 microM-0.7 microM. The virucidal property of these conjugates suggests that a cocktail of anti-HIV-1 PNA-MTD peptide conjugates targeting critical regions of the HIV-1 genome could serve as a prophylactic agent for inactivating HIV-1 virions after exposure to HIV-1.