[Synthesis, conformation, and spectroscopy of nucleoside analogues concerning their antiviral activity]. / Synteza, konformacja i spektroskopia analogów nukleozydów oraz ich aktywnosc antywirusowa.

Chemically modified analogues of nucleosides and nucleotides, have been thoroughly investigated since the discovery of DNA double helix by Watson and Crick in 1953 (Nature 171: 737). Chemical structures, first of all tautomerism, of the nucleic acid bases, as well as the conformations of the nucleic acids constituents, determine the secondary and tertiary structures of DNA and RNA polymers. Similarly, structural and dynamic parameters of nucleoside derivatives determine their biological activity in mutagenesis, neoplastic transformation, as well as antiviral or anticancer properties. In this review, a multidisciplinary approach of Prof. David Shugar's group is presented in the studies on nucleosides and nucleotides. It consists in chemical syntheses of suitable analogues, measurements of physicochemical and spectral parameters, conformational analysis by means of nuclear magnetic resonance (NMR) and X-ray diffraction, as well as characteristics of the nucleoside analogues as inhibitors of some selected, target enzymes, crucial in respect to antiviral activity of the analogues. These long-lasting studies follows upon the line of the main paradigm of molecular biophysics, i. e. structure-activity relationship.

[Purine and pyrimidine nucleoside phosphorylases - remarkable enzymes still not fully understood]. / Nukleozydowe fosforylazy purynowe i pirymidynowe - niezwykle enzymy ciagle nie do konca rozszyfrowane.

Purine and pyrimidine nucleoside phosphorylases catalyze the reversible phosphorolytic cleavage of the glycosidic bond of purine and pyrimidine nucleosides, and are key enzymes of the nucleoside salvage pathway. This metabolic route is the less costly alternative to the de novo synthesis of nucleosides and nucleotides, supplying cells with these important building blocks. Interest in nucleoside phosphorylases is not only due to their important role in metabolism of nucleosides and nucleotides, but also due to the potential medical use of the enzymes (all phosphorylases in activating prodrugs - nucleoside and nucleic base analogs, high-molecular mass purine nucleoside phosphorylases in gene therapy of some solid tumors) and their inhibitors (as selective immunosuppressive, anticancer and antiparasitic agents, and preventing inactivation of other nucleoside drugs). Phosphorylases are also convenient tools for efficient enzymatic synthesis of otherwise inaccessible nucleoside analogues. In this paper the contribution of Professor David Shugar and some of his colleagues and coworkers in studies of these remarkable enzymes carried out over nearly 40 years is discussed on the background of global research in this field.

Ten paths to the discovery of antivirally active nucleoside and nucleotide analogues.

Nucleoside and nucleotide analogues have proven to be an effective approach toward the development of antiviral compounds. This approach has so far yielded a number of clinically useful antiviral drugs, such as BVDU (brivudin), (val)aciclovir, cidofovir, adefovir dipivoxil, and tenofovir disoproxil fumarate, and current perspectives justify the further development of other nucleoside analogues, such as FV-100, and that of the DAPy-based nucleotide analogues, the 5-aza analogue of cidofovir, and prodrug derivatives thereof.

Application of kinase bypass strategies to nucleoside antivirals.

Nucleoside and nucleotide analogs have served as the cornerstones of antiviral therapy for many viruses. However, the requirement for intracellular activation and side-effects caused by distribution to off-target sites of toxicity still limit the efficacy of the current generation of drugs. Kinase bypass strategies, where phosphorylated nucleosides are delivered directly into cells, thereby, removing the requirement for enzyme catalyzed phosphorylation steps, have already changed the face of antiviral therapy in the form of the acyclic nucleoside phosphonates, cidofovir, adefovir (given orally as its dipivoxil prodrug) and tenofovir (given orally as its disoproxil prodrug), currently used clinically. These strategies hold further promise to advance the field of antiviral therapy with at least 10 kinase bypass and tissue targeted prodrugs, representing seven distinct prodrug classes, currently in clinical trials. This article reviews the history of kinase bypass strategies applied to nucleoside antivirals and the evolution of different tissue targeted prodrug strategies, highlighting clinically relevant examples.