Potency of a small molecule that targets the molluscum contagiosum virus processivity factor increases when conjugated to a tripeptide.

We recently developed compound FC-7269 for targeting the Molluscum contagiosum virus processivity factor (mD4) and demonstrated its ability to inhibit viral processive DNA synthesis in vitro and cellular infection of an mD4-dependent virus (Antiviral Res 211, 2023,105520). However, despite a thorough medicinal chemistry campaign we were unable to generate a potent second analog as a requisite for drug development. We overcame this impasse, by conjugating a short hydrophobic trivaline peptide to FC-7269 to produce FC-TriVal-7269 which significantly increased antiviral potency and reduced cellular toxicity. • The small molecule 7269 is the first antiviral specific for Molluscum contagiosum. • Exhaustive med chem failed to generate a second compound for drug development. • The impasse was solved by conjugating a Tri-Valine peptide to 7269. • The TriVal-7269 molecule has greater antiviral potency and is not toxic to cells. • Peptide-conjugated drugs represent a new approach to antiviral drug development. [ABSTRACT FROM AUTHOR]