Extended Substrate Acceptance of Herpes Simplex Virus Type 1 Thymidine Kinase: a New Chance for Gene and Antiviral Therapy

Abstract

Herpes simplex virus type 1 thymidine kinase (HSV1-TK) has become increasingly important as a target in medicinal chemistry because of its links to therapy of viral infection, gene therapy of cancer and allogeneic transplantation. These applications are based on the differences in binding properties between the human and the viral enzyme. Several problems have been encountered in the clinic, e.g. the increase of resistance for antiviral drugs and the immunosuppressive effects of the dosages needed for tumor regression. Thus intensive efforts have been directed towards understanding substrate diversity to overcome the clinical limitations. In this context, kinetic and thermodynamic studies revealed that substrates bind in compulsory order and that the binding event is enthalpy driven. The structural evaluation of aciclovir resistant HSV strains shows that loss of electrostatic interactions, change in steric accessibility and modification of the 3D conformation of HSV1-TK are responsible for the encountered resistance. Further crystallography studies revealed the role of water in substrate binding, the advantage of a fixed ribose ring and that substrate acceptance of HSV1-TK is extended to all five nucleobases. The reviewed results give new rationale for the design of novel prodrugs and engineered HSV1-TK for antiviral and gene therapy.