Cellular metabolism and enzymatic phosphorylation of 9-(2-phosphonylmethoxyethyl) guanine (PMEG), a potent antiviral agent.

Abstract

PMEG (9-(2-Phosphonylmethoxyethyl)guanine) is a potent, broad spectrum antiviral agent in the nucleoside phosphonate class (Figure 1). In vitro, PMEG is active against HSV-1, HSV-2, VZV, HCMV and Rauscher murine leukemia virus with IC50s (the concentrations of drug required to reduce the plaque formation by 50%) less than 1 ug/ml (1,2,3). Similar antiviral activity was demonstrated with TK-minus mutants of HSV-1. However, the toxic effect exerted by PMEG on CEM and Vero cells in culture (TC50 5-10 μg/ml, the concentrations of drug affecting the viability of uninfected cells by 50%) limits the utility of PMEG as an antiviral agent. On the other hand, PMEG has antitumor activity (4) against intraperitoneal P388 leukemia and subcutaneously implanted B16 melanoma in mice. PMEG, also supresses human condylomas from papillomavirus (HPV-11) infected human foreskin in transplanted mice (5). We have investigated the cellular metabolism of PMEG and the viral and cellular target enzymes involved in the mode of action to provide rationale for the low antiviral selectivity and to assist with future design of more selective analogs of PMEG.