Selective inhibition of human cytomegalovirus replication by a novel nucleoside, oxetanocin G

Abstract

A novel nucleoside with an oxetanosyl-N-glycoside has been recently isolated from a culture filtrate from Bacillus megaterium and named oxetanocin A (N. Shimada, S. Hasegawa, T. Harada, T. Tomisawa, A. Fujii, and T. Takita, J. Antibiot. 39:1623-1625, 1986). In this study, we evaluated the antiherpesvirus activity of oxetanocin A and its derivatives and found that 9-(2-deoxy-2-hydroxymethyl-beta-D-erythro-oxetanosyl)guanine (OXT-G) was very potent and selective in inhibiting the replication of human cytomegalovirus (HCMV) in vitro. The median effective concentration for HCMV strain AD169 was 1.0 microgram/ml, and that for herpes simplex virus type 2 strain 186 was 3.5 micrograms/ml. The selectivity index, based on the ratio of the median inhibitory concentration for cell growth of human diploid fibroblasts to the median effective concentration for HCMV plaque formation, was more than 300. The synthesis of HCMV-induced late polypeptides such as the 150,000-molecular-weight capsid and the 68,000-molecular-weight major matrix proteins was strongly suppressed when OXT-G (5 micrograms/ml) was added to the cultures at the beginning of infection. At this concentration of OXT-G, the amount of HCMV DNA detected in the drug-treated infected cells was less than 1/10 of that detected in the infected control cells. The results suggest that the mode of action of OXT-G is inhibition of viral replication by impairing the viral DNA synthesis.