PEPTIDOMIMETIC INHIBITORS OF HERPES-SIMPLEX VIRUS RIBONUCLEOTIDE REDUCTASE - A NEW CLASS OF ANTIVIRAL AGENTS

We have been investigating a new class of antiviral compounds effectiv e against herpes simplex virus (HSV) in vitro and in vivo. Antiviral a ctivity results from inhibition of HSV ribonucleotide reductase (RR). The inhibitors are designed as mimics of the RR small subunit C-termin us, a region essential for RR subunit association and consequently enz ymatic activity. Inhibition results from specific binding of the inhib itor to the HSV RR large subunit thereby preventing subunit associatio n. This report details the structure-activity studies that lead to the identification of BILD 1263, a potent inhibitor of HSV RR subunit ass ociation (IC50, 0.2 nM) that also inhibits the replication of HSV type s 1 and 2 in cell culture (EC(50), 3 and 4 mu M) and reduces the sever ity of HSV-1-induced keratitis in a murine ocular model. The discovery of inhibitors with in vitro antiviral activity results from a combina tion of improving inhibitor potency in a RR binding assay and modifyin g inhibitor physicochemical properties. The importance and possible ro le of the new structural modifications introduced into this inhibitor series is discussed.