Specific inhibition of paramyxovirus and myxovirus replication by oligopeptides with amino acid sequences similar to those at the N-termini of the F_l or HA₂ viral polypeptides

A series of oligopeptides have been synthesized with amino acid sequences that resemble those of the N-terminal regions of the paramyxovirus F₁, polypeptide or the myxovirus HA₂ polypeptide, N-termini generated by proteolytic cleavage which activates infectivity. Oligopeptides with the appropriate structure are highly active, specific inhibitors of the infectivity of each virus, and of cell fusion and hemolysis induced by paramyxoviruses. Structure-activity studies have revealed the following characteristics of the inhibitory activity. Inhibition is amino acid sequence specific, and the presence of the same N-terminal amino acid on the oligopeptide as the viral polypeptide is crucial for activity. Longer peptides are more active than shorter ones with the same initial sequence. The presence of a carbobenzoxy group (Z) on the N-terminal amino acid of the oligopeptide increases inhibitory activity, and the addition of a methyl group to the carboxyl moiety of the C-terminal amino acid decreases activity. The steric configuration of the first two amino acids has a significant effect; optimum activity was obtained with oligopeptides beginning with Z-d-phenylalanine-l-phenylalanine. The results suggest that the oligopeptides competitively interfere with the N-terminal region of the F₁ or HA₂ polypeptides of paramyxoviruses or myxoviruses, respectively. The availability of these oligopeptide inhibitors provides an additional means for determining the exact site and mechanism by which the F₁ and HA₂ polypeptides initiate infection, and for investigating the biochemical and physical events in virus-induced cell fusion and hemolysis, and membrane fusion in general. The finding of specific inhibition of infectivity by oligopeptides which resemble a region of a viral polypeptide also provides a possible new approach to chemical inhibition of viral replication.