Optimization of Inhibitory Peptides Targeting Phosphoprotein of Rabies Virus

Rabies is a serious zoonosis caused by rabies virus (RABV) of the genus Lyssavirus, and immunotherapy is now the only approved, effective method for post-exposure prophylaxis against rabies in humans, whereas an effective antiviral therapy is still unavailable if the central nervous system is invaded. Phosphoprotein (P) is known to play pivotal roles in the life cycle of RABV, and has been regarded as a prime target for inhibitors of viral replication. This study aimed to carry out intracellular administration of a kind of P-binding peptide for RABV inhibition. A group of reported P-binding peptides were focused on for activity improvement by quantitative structure–activity relationship (QSAR) method, and then were mediated by cell penetrating peptide (CPP) for intracellular activity evaluation. The QSAR models had good performance in reliability and predictability (R(2) ≥ 0.852, Q(2) ≥ 0.601, [Formula: see text] ≥ 0.595), and the peptide screened by partial least squares (PLS) QSAR model (R(2) = 0.994, Q(2) = 0.937, [Formula: see text] = 0.981) exhibited even higher antiviral activity when it was delivered into the cells by CPP. Above all, this study provided an effective way for development of peptide drug against RABV.