Structure-activity relationships and conformational features of antiherpetic pyrimidine and purine nucleoside analogues. A review

Abstract

A rational approach to the design of antiherpetic nucleoside analogues is based in part on the broad specificity of virus-coded thymidine kinases. Herpes virus thymidine kinase 'activates' many 5-substituted 2'-deoxyuridines, analogues of thymidine (e.g., idoxuridine, trifluridine, edoxudine, brivudine), 5-substituted arabinofuranosyluracil derivatives (e.g., 5-Et-Ara-U, BV-Ara-U, Cl-Ara-U), acyclonucleosides of guanine (e.g., aciclovir, ganciclovir, penciclovir), and purine nucleosides with the pentafuranosyl ring replaced by a cyclobutane ring (e.g., cyclobut-G, cyclobut-A). Activation involves selective, and frequently regiospecific, phosphorylation of these analogues to the 5'-monophosphates. These are further phosphorylated by cellular enzymes to the 5'-triphosphates, which are usually competitive inhibitors of the viral-coded DNA polymerases. Some analogues are also incorporated into viral, and to a lesser extent cellular, DNA. A recent, unusual, exception is human cytomegalovirus, which does not code for a thymidine kinase, but for a protein with the sequence characteristics of protein kinase and which phosphorylates ganciclovir to its 5'-monophosphate. The interaction of the analogues with cellular catabolic enzymes such as uridine and thymidine nucleoside phosphorylases is also discussed, as is the relationship between physicochemical properties (configuration, conformation, electronic and hydrophobic parameters) and antiviral activities, with particular reference to those drugs that are licensed, or under consideration, for clinical use.

Functional differences in nucleoside and nucleobase transporters expressed on the rabbit corneal epithelial cell line (SIRC) and isolated rabbit cornea

“…The corneal epithelium consists of 5 to 6 layers of columnar epithelial cells that form tight junctions, 5 limiting paracellular diffusion. Since a large number of naturally occurring nucleoside and nucleoside analogs are hydrophilic, 6 transcellular diffusion is also low, thereby limiting the effectiveness of these antiviral agents. In the absence of specialized transport systems, the passage of hydrophilic molecules across the corneal epithelium is thus limited.…”

A pseudoreceptor modelling study of the varicella-zoster virus and human thymidine kinase binding sites

“…8 for a not greatly affect the overall conformation of a molecule [9]. MNDO [lo] electrostatic potential charges were generated for all geometry-optimised ligands.…”

Anti‐DNAVirus Agents

“…Among them the first more broadly used antivirals are 5-iodo-2 0 -deoxyuridine (idoxuridine) (Herpid Ò , Stoxil Ò , 1) [14,15] and 5-trifluoromethyl-2 0 -deoxyuridine (trifluridine) (Viroptic Ò , 2) [16]. Both drugs are aimed at the use in ophthalmology (keratoconjunctivitis caused by HSV).…”