POTENT INHIBITION OF HERPES-SIMPLEX-VIRUS BY MDL-101028, A NOVEL BIPHENYL DISULFONIC ACID UREA COPOLYMER

A novel low-molecular-weight sulfonic acid polymer, MDL 101028, was in vestigated for antiviral activity against herpes simplex virus (HSV) t ype 1 and type 2 in human embryonic diploid fibroblasts (MRC-5) and in a line of monkey kidney cells (Vero). Potent antiviral activities wer e obtained when treatment was restricted to the adsorption phase of vi rus propagation as measured by plaque reduction assay, and this was co nfirmed by experiments at high multiplicity of infection. Inhibition o f virus binding to host cells by MDL 101028 was compared to that of he parin, a known antagonist of virus attachment. Both compounds showed d ose-dependent inhibition, with IC50 values of 1.1 and 0.43 mu g ml(-1) , respectively. The effect on cell-to-cell fusion was investigated usi ng a syncytial-positive (syn(+)) phenotypic mutant of HSV-1 (strain 17 i). MDL 101028 (3-10 mu M) dramatically halted the spread of syncytial lesions; this effect was accompanied by the destruction of the syncyt ium and regrowth into the lesion by uninfected Vero cells. In contrast , heparin (10 mu g ml(-1)) only partially reduced the spread of syncyt ia. Protection was also observed with MDL 29797 (100 mu g ml(-1)), an antagonist of glycoprotein maturation. Unexpectedly, only a marginal e ffect was observed with acyclovir (10 mu g ml(-1)), a potent inhibitor of viral DNA synthesis and HSV growth. As an extension to the current therapy for herpes simplex infection, acyclovir, the potent antifusio n activity of MDL 101028 may have a clinical use tissues or organs in which cell-to-cell fusion contributes to the pathology.