CYCLOCREATINE (1-CARBOXYMETHYL-2-IMINOIMIDAZOLIDINE) INHIBITS THE REPLICATION OF HUMAN HERPES VIRUSES

The creatine kinase/creatine phosphate (CK/CrP) system plays an import ant role in cellular energy homeostasis. CK isoenzymes, which reversib ly generate ATP from CrP, are compartmentalized at cellular sites wher e energy is produced or utilized. It has been noted that the expressio n of CK is induced in cells infected by several DNA viruses, implicati ng a role for cellular energy modulation as an important step for effi cient viral replication. A CK substrate analog, 1-carboxymethyl-2-imin oimidazolidine (cyclocreatine; CCr), was tested in vitro for antiviral activity against a variety of herpes viruses and RNA viruses. Several members of the human herpes virus family were found to be sensitive t o CCr, including herpes simplex types 1 and 2 (HSV-1 and HSV-2), varic ella-zoster virus, and cytomegalovirus. When administered to mice infe cted vaginally with HSV-2, CCr significantly reduced mortality, reduce d vaginal lesion scores, and lowered the titers of recoverable virus. This treatment combined with acyclovir appeared to enhance the antivir al effects of acyclovir. In a second model, mice infected intraperiton eally with HSV-2 and treated with CCr showed a significant increase in survival compared to placebo. We conclude that CCr is the first examp le of a new class of antiviral compounds that target the CK/CrP system .