Sub-stoichiometric Modulation of Viral Targets-Potent Antiviral Agents That Exploit Target Vulnerability

The modulation of oligomeric viral targets at sub-stoichiometric ratios of drug to target has been advocated for its efficacy and potency, but there are only a limited number of documented examples. In this Viewpoint, we summarize the invention of the HIV-1 maturation inhibitor fipravirimat and discuss the emerging details around the mode of action of this class of drug that reflects inhibition of a protein composed of 1,300-1,600 monomers that interact in a cooperative fashion. Similarly, the HCV NS5A inhibitor daclatasvir has been shown to act in a highly sub-stoichiometric fashion, inhibiting viral replication at concentrations that are ∼23,500 lower than that of the protein target.