Progress in the Clinical Management of Herpesvirus Infections

Abstract

SummaryAntiviral drug discovery has produced a series of drugs active against herpesviruses in vitro. Several of these are now licensed and/or have been used in clinical practice. This article reviews the mechanisms· of action of acyclovir, ganciclovir, penciclovir, sorivudine and foscarnet, the development of resistance to these drugs and their pharmacokinetic and cellular toxicities. Based upon the natural histories of HSV, VZV and CMV, treatment objectives for each virus are discussed and the performance of each drug matched against these objectives. Overall, it is concluded that the perfect drug for treating herpesviruses does not exist, but that significant progress has been made towards controlling several herpesvirus diseases. It.is suggested that further progress will require not just improved drug discovery programmes, but also an understanding of different pathogeneses and an appreciation by practising physicians that antiviral drugs must be given early in the infectious process to achieve the best results.

CRE recombinase-based positive–negative selection systems for genetic manipulation in Trypanosoma brucei

“…We chose to employ the well-studied Herpes simplex virus thymidine kinase (HSVTK) (EC 2.7.1.21) [36] as a negative selectable marker that had been used previously in bloodstream forms of T. brucei [37]. HSVTK phosphorylates nucleosides more promiscuously than its cellular homologues, rendering cells that express it sensitive to nucleoside analog prodrugs such as GCV.…”

Enzymatic and Structural Analysis of Inhibitors Designed against Mycobacterium tuberculosis Thymidylate Kinase

“…Acyclovir is phosphorylated by several viral or host kinases into acyclovir triphosphate, which terminates DNA synthesis when incorporated into the viral DNA (5,6). The comparative x-ray structures of different enzyme-ligand complexes of HSV type 1 thymidine kinase (7-10) revealed a number of interesting structural features and paved the way for rational structure-based drug design of antiviral compounds (11,12).…”

“…a continuous chain of several side chains in line and sharing a proton including W13, Glu 6 , Ser 99 , Arg 95 , and Asp 9 (Fig. 6).…”

Valganciclovir Results in Improved Oral Absorption of Ganciclovir in Liver Transplant Recipients

“…Ganciclovir (GCV), given intravenously (i.v.) at 5 mg/kg of body weight once daily, or orally as capsules at 1,000 mg three times a day (TID), is the standard drug regimen for both the treatment and prevention of CMV disease in transplant recipients (11,15). However, i.v.…”