Nucleoside inhibitors

Adenylyl Cyclases. Table 3 Nucleoside inhibitors of adenylyl cyclase. Assays were with a detergent-dispersed adenylyl cyclase from rat brain and were with 100 pM 5 ATn and 5 mM MnCI2 as substrates... 

Olsen DB (2006) Potent nucleoside inhibitors of HCV RNA replication SAR and other lessons learned. In 17th international roundtable on nucleosides, nucleotides and nucleic acids, Bern, Switzerland... 

Nucleoside inhibitors of hepatitis C virus RNA polymerase improved potency and liver targeting with 7-deaza-7-fluoro-2 -C-methyladenosine. In Late breaker presentations. 20th international conference on antiviral research, Palm Springs, CA, USA, April 29-May 3, 2007, LB-01... 

Non-nucleoside inhibitors JTK003 B1LB1941 P495A/L/S/T, P496A/S, V499A... 

As for HIV, the selection of HCV drug resistant variants can be accompanied by a decrease in RC. For HCV protease inhibitor resistant variants, the level of resistance seems to be inversely related to viral fitness (Sarrazin et al. 2007 Tong et al. 2006 Yi et al. 2006). There is some evidence that viral RC can be restored by the selection of compensatory mutations within the protease gene (Sarrazin et al. 2007 Tong et al. 2006 Yi et al. 2006). However, further research is warranted to investigate to what extent viral fitness can be restored and by which mutations. Also for the nucleoside and non-nucleoside inhibitors, the selection of resistance results in a fitness defect. It remains to be investigated whether or not compensatory mutations can be selected. 

Kukolj G, McGibbon GA, McKercher G, Marquis M, Lefebvre S, Thauvette L, Gauthier J, Goulet S, Poupait MA, Beaulieu PL (2005) Binding site characterization and resistance to a class of non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase, J Biol Chem 280 39260-39267... 

R1626 (prodrug of R1479) Non-nucleoside inhibitor Roche Phase 2... 

Williams TM, Ciccarone TM, MacTough SC, Rooney CS, Balani SK, Con-dra JH, Emini EA, Goldman ME, Greenlee WJ, Kauffman LR, O Brien JA, Sardana VV, Schleif WA, Theoharides AD, Anderson PS. 5-Chloro-3-(phe-nylsulfonyl)indole-2-carboxamide a novel, non-nucleoside inhibitor of HIV-1 reverse transcriptase. J Med Chem 1993 36 1291-1294. 

Saag MS, Emini EA, Laskin OL, Douglas J, Lapidus WI, Schleif WA, Whitley RJ, Hildebrand C, Byrnes VW, Kappes JC, Anderson KW, Massari FE, Shaw GM, the L-697,661 Working Group. A short-term clinical evaluation of L-697,661, a non-nucleoside inhibitor of HIV-1 reverse transcriptase. N Engl J Med 1993 329 1065-1072. 

Mellors JW, Dutschman GE, Im G-J, Tramontano E, Winkler SR, Cheng Y-C. In vitro selection and molecular characterization of human immunodeficiency virus-1 resistant to non-nucleoside inhibitors of reverse transcriptase. Mol Pharmacol 1992 41 446-451. 

Jorgensen, W. L. Ruiz-Caro, J. Tirado-Rives, J. Basavapathruni, A. Anderson, K. S. Hamilton, A. D. Computer-aided design of non-nucleoside inhibitors of HIV-1 reverse transcriptase. Bioorg. Med. Chem. Lett. 2006,16, 663-667... 

The non-nucleoside inhibitors of reverse transcriptase (nevirapine, dela-virdine, efavirenz) are not phosphory-lated. They bind to the enzyme with high selectivity and thus prevent it from adopting the active conformatioa Inhibition is noncompetitive. 

Figure 1.5 Selected small molecule inhibitors of DNMTs. 1 and 2 are irreversible nucleoside inhibitors while 3, 4, 5 and 6 are reversible small molecule inhibitors.

Zalcitabine (ddC, Hivid) is a cytidine analogue active against HIV-1, HIV-2, and hepatitis B virus. It is used for the treatment of HIV infection in adults and asymptomatic children as part of a multidrug regimen. It may be less effective than the other nucleoside inhibitors and is used less frequently. 

ZD-9331 is a non-nucleosidic inhibitor of thymidylate synthase. It is also an antifolate, in which the quinazoline moiety replaces the pteridine entity, structurally close to methylene tetrahydrofolate (i.e., the second substrate of thymidylate synthase). Moreover, replacement of the acid function of glutamic acid by a tetrazole renders polyglutamination impossible. Consequently, ZD-9331 is active on tumors that are resistant to the usual antifolates. ... 

Esnouf R, Ren J, Ross R, Jones Y, Stammers D, Stuart D. Mechanism of inhibition of HIV-1 reverse transcriptase by non-nucleoside inhibitors. Nature Struct Biol 1995 2 303-308. 

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