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 tRNA₃^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 IC₅₀ values for virucidal activity were in the range of ∼ 50 nM; IC₅₀ values for inhibition of HIV-1 replication/infection were 0.5 μM-0.7 μM. 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.