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Antimicrobial Agents and Chemotherapy, June 2007, p. 2028-2034, Vol. 51, No. 6
0066-4804/07/$08.00+0     doi:10.1128/AAC.01284-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Sensitivity of Monkey B Virus (Cercopithecine herpesvirus 1) to Antiviral Drugs: Role of Thymidine Kinase in Antiviral Activities of Substrate Analogs and Acyclonucleosides{triangledown}

Federico Focher,1 Andrea Lossani,1 Annalisa Verri,1 Silvio Spadari,1 Andrew Maioli,2 Joseph J. Gambino,2 George E. Wright,2* Richard Eberle,3 Darla H. Black,3 Peter Medveczky,4 Maria Medveczky,4 and David Shugar5

Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, 27100 Pavia, Italy,1 GLSynthesis Inc., Worcester, Massachusetts 01605,2 Department of Veterinary Pathobiology, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, Oklahoma 74078,3 Department of Microbiology and Immunology, College of Medicine, University of South Florida, Tampa, Florida 33620,4 Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland5

Received 13 October 2006/ Returned for modification 27 December 2006/ Accepted 2 March 2007

Herpes B virus (B virus [BV]) is a macaque herpesvirus that is occasionally transmitted to humans where it can cause rapidly ascending encephalitis that is often fatal. To understand the low susceptibility of BV to the acyclonucleosides, we have cloned, expressed, and characterized the BV thymidine kinase (TK), an enzyme that is expected to "activate" nucleoside analogs. This enzyme is similar in sequence and properties to the TK of herpes simplex virus (HSV), i.e., it has a broad substrate range and low enantioselectivity and is sensitive to inhibitors of HSV TKs. The BV enzyme phosphorylates some modified nucleosides and acyclonucleosides and L enantiomers of thymidine and related antiherpetic analogs. However, the potent anti-HSV drugs acyclovir (ACV), ganciclovir (GCV), and 5-bromovinyldeoxyuridine were poorly or not phosphorylated by the BV enzyme under the experimental conditions. The antiviral activities of a number of marketed antiherpes drugs and experimental compounds were compared against BV strains and, for comparison, HSV type 1 (HSV-1) in Vero cell cultures. For most compounds tested, BV was found to be about as sensitive as HSV-1 was. However, BV was less sensitive to ACV and GCV than HSV-1 was. The abilities of thymidine analogs and acyclonucleosides to inhibit replication of BV in Vero cell culture were not always proportional to their substrate properties for BV TK. Our studies characterize BV TK for the first time and suggest new lead compounds, e.g., 5-ethyldeoxyuridine and pencyclovir, which may be superior to ACV or GCV as treatment for this emerging infectious disease.

* Corresponding author. Mailing address: GLSynthesis Inc., One Innovation Drive, Worcester, MA 01605. Phone: (508) 754-6700. Fax: (508) 754-7075. E-mail: george.wright{at}glsynthesis.com

{triangledown} Published ahead of print on 6 April 2007.

Antimicrobial Agents and Chemotherapy, June 2007, p. 2028-2034, Vol. 51, No. 6
0066-4804/07/$08.00+0     doi:10.1128/AAC.01284-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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