Simplified θ-defensins: Search for new antivirals

Peptides of the innate immune system provide intriguing templates for designing novel antiviral molecules. θ-defensins are nonhuman primate peptides with broad-spectrum antiviral activities. The activity of these compounds is mediated through interference with viral fusion, and this activity is based upon key structural features. However, two major limitations to their clinical use hampered their development as potential antivirals, namely difficult multi-step synthesis for their production with low final yield of desired product (~5%), and unfavorable pharmacokinetics (rapid enzymatic degradation and/or renal clearance). Recently we designed and screened two sub-libraries of new peptide-based entry inhibitors mimicking the structure of humanized θ-defensins, designated as Hapivirins (HpVs) and Diprovirins (DpVs). Although the new peptides are smaller (13-residues) and structurally more simple than retrocyclins, several retained their ability to protect cells from infection by HIV-1 and HSV-2. The most active compound, DpV16, was chosen for a second round of modifications based on (1) its potent antiviral activity (2) its ease of synthesis, and (3) the low cost of production. Subsequently, we created a library of a second generation DpV-analogues with enhanced properties. Collectively, our findings to date suggest that simplified θ-defensins are suitable candidates for further modifications to obtain analogues with clinically favorable pharmacokinetics that may be produced in large quantities using a standard chemical approach. Considering their small size, they could be used either topically (topical microbicides) and/or for systemic applications (entry inhibitors).