[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.

[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.

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.

[Anti-HIV nucleoside drugs: retrospective view at future].

This review provides data on the design of antiretroviral drugs based on nucleoside analogs. About 30 drugs were approved for the treatment of HIV-infected patients over 25 years. Seven nucleoside drugs are inhibitors of HIV reverse transcriptase and clinically used in combination with inhibitors of other viral enzymes, integrase and protease, and non-nucleoside inhibitors of reverse transcriptase. Toxicity of nucleoside drugs and approaches to obtaining of safe anti-HIV drugs are discussed. The results of developing of domestic anti-HIV drugs are presented. The future prospects of anti-HIV investigations are considered.

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.

The acyclic nucleoside phosphonates from inception to clinical use: historical perspective.

The collaboration between Antonín Holý [Institute of Organic Chemistry and Biochemistry (IOCB, Prague, Czech Republic)] and Erik De Clercq (Rega Institute for Medical Research, K.U. Leuven, Belgium) started exactly 30 years ago. It led to the discovery of a (rather small) series of acyclic nucleoside analogues (prototype: DHPA), followed by the discovery of a large number of nucleotide analogues [acyclic nucleoside phosphonates (ANPs)] (prototype: HPMPA). From HPMPA originated three compounds, which have been approved by regulatory agencies worldwide for clinical use: (i) HPMPC [cidofovir (Vistide)] for the treatment of cytomegalovirus (CMV) retinitis in AIDS patients, and "off label" for the treatment of polyoma-, papilloma-, adeno-, herpes- and poxvirus infections; (ii) PMEA [adefovir (in its oral prodrug form, adefovir dipivoxil (Hepsera)] for the treatment of chronic HBV (hepatitis B virus) infections, and (iii) PMPA [tenofovir (in its oral prodrug form, tenofovir disoproxil fumarate (Viread)] for the treatment of HIV infections (AIDS). The latter has also been approved, in combination with emtricitabine (Truvada), and in combination with emtricitabine and efavirenz (Atripla((R))) for the treatment of HIV infections. Many other ANPs such as the DAP derivatives HPMPDAP, PMEDAP and PMPDAP, and the DAPy derivatives HPMPO-DAPy, PMEO-DAPy, and PMPO-DAPy, were found to exhibit an antiviral activity spectrum and potency comparable to that of the parent compounds HPMPA (and HPMPC), PMEA and PMPA, respectively.