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New helicase-primase inhibitors as drug candidates for the treatment of herpes simplex disease

Nature Medicine volume 8, pages 392–398 (2002)Cite this article

Abstract

The vast majority of the world population is infected with at least one member of the human herpesvirus family. Herpes simplex virus (HSV) infections are the cause of cold sores and genital herpes as well as life-threatening or sight-impairing disease mainly in immunocompromized patients, pregnant women and newborns. Since the milestone development in the late 1970s of acyclovir (Zovirax), a nucleosidic inhibitor of the herpes DNA polymerase, no new non-nucleosidic anti-herpes drugs have been introduced. Here we report new inhibitors of the HSV helicase-primase with potent in vitro anti-herpes activity, a novel mechanism of action, a low resistance rate and superior efficacy against HSV in animal models. BAY 57-1293 (N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4- (2-pyridinyl)phenyl]acetamide), a well-tolerated member of this class of compounds, significantly reduces time to healing, prevents rebound of disease after cessation of treatment and, most importantly, reduces frequency and severity of recurrent disease. Thus, this class of drugs has significant potential for the treatment of HSV disease in humans, including those resistant to current medications.

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Figure 1: Antiviral effect of inhibitors in vitro.
Figure 2: Compounds inhibit early and late gene expression.
Figure 3: Potency and efficacy of compounds in HSV-infected mice.
Figure 4: Potency and efficacy of compounds in HSV-2-infected guinea pigs. Suppression of acute disease symptoms (photographed at d6 p.i.) of 10 vaginally infected (2.5 × 105 p.f.u. HSV-2 strain MS) female guinea pigs per group.

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Acknowledgements

We thank J. Blümel for clinical field isolates (UB1-31, UB33-47 & UB49-56) of HSV-1 and HSV-2; P. Spear and L. Kwan for analyzing herpesvirus entry into cells; P. Schaeffer for ICP-4 plasmids; S. Weller for recombinant baculoviruses; H.R. Hehnen for material and lab space to carry out the animal virus experiments (equine, porcine and bovine herpes strains).; M. Becka for statistical analysis of data; and K. Ostertag-Palm, M. Hucke, C. Stamm, E. Clemente, M. Werth, J. Wann, I. Hulsmann, S. Schaab, S. Vogel, S. Veldhoen, D. Ganzer, G. Köppe, J. Hotho, J. Leske, U. Zuther, H. Schoop, O. Augustin, M. Peters, J. Dornieden, H. Blum, E. Lindner, G. Heckmann, E. Carrozzo, B. Schulz, H. Küper, U. Reimann, M. Heidtmann, D. Höpker, A. Haas, A. Rudek, J. Daheim, J. Verlage, B. Poschmann, M. Heine and P. Hartmann for technical assistance.

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  1. Bayer AG, Pharma Research, Wuppertal, Germany

    Gerald Kleymann, Rüdiger Fischer, Ulrich A.K. Betz, Martin Hendrix, Wolfgang Bender, Udo Schneider, Gabriele Handke, Peter Eckenberg, Guy Hewlett, Veniamin Pevzner, Judith Baumeister, Olaf Weber, Kerstin Henninger, Jörg Keldenich, Axel Jensen, Jörg Kolb, Ute Bach, Andreas Popp, Jutta Mäben, Isabelle Frappa, Dieter Haebich, Oswald Lockhoff & Helga Rübsamen-Waigmann

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Correspondence to Gerald Kleymann.

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Kleymann, G., Fischer, R., Betz, U. et al. New helicase-primase inhibitors as drug candidates for the treatment of herpes simplex disease. Nat Med 8, 392–398 (2002). https://doi.org/10.1038/nm0402-392

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