Polymerase inhibitors

In contrast to retroviruses, proteolysis is an early event in the replication cycle of (+)-strand RNA viruses and both protease and polymerase inhibitors can be expected to halt the propagation of infectious viral particles from already infected cells. 

These modified Rosenmund von Braun reaction conditions were also used by Gopalsamy et al. for the rapid cyanation of the 1,3,4,9-tetrahydropyrano-[3,4-fc]indole skeleton while searching for potent and selective Hepatitis C virus polymerase inhibitors (Scheme 74) [84]. 

Mo H, Lu L, Pilot-Matias T, PithawaUa R, Mondal R, Masse S, Dekhtyar T, Ng T, Koev G, StoU V, Stewart KD, Pratt J, Donner P, Rockway T, Mating C, Molla A (2005) Mutations conferring resistance to a hepatitis C vims (HCV) RNA-dependent RNA polymerase inhibitor alone or in combination with an HCV serine protease inhiltitor in vitro. Antimicrob Agents Chemother 49 4305 314... 

Toniutto P, Fabris C, Bitetto D, Fornasiere E, Rapetti R, Pirisi M (2007) Valopicitabine dihydrochloride a specific polymerase inhibitor of hepatitis C virus. Curr Opin Investig Drags 8 150-158... 

To summarize, terminase inhibitors point the way toward a switch in strategy for developing HCMV inhibitors, with the aim of achieving a quality different from that of established DNA polymerase inhibitors. Intervention with viral DNA maturation arrests the replicative cycle at the DNA cleavage and packaging step, leading to an accumulation of empty procapsids and unprocessed concatemeric DNA. 

Terminase inhibition is an antiviral approach that may also be of consequence for other members of the herpesvirus group. In addition, since a similar DNA maturation process does not occur in higher cells, this principle offers the potential for high selectivity, in contrast to many of the viral DNA polymerase inhibitors, which also interact with cellular enzymes and hence can have severe side effects. 

Fig. 4 Rephcation cycle of HBV illustrating the site of action of polymerase inhibitors and heteroaryl dihydropyrimidine (HAP) assembly inhibitors such as BAY 41 109...

Currently, there is no approved antiviral therapy specifically targeting hepatitis C virus (HCV). The development of an HCV replicon system and our improved understanding of the structure and function of HCV proteins have led to the development of several classes of specific HCV inhibitors. NS3-4A protease inhibitors and NS5B polymerase inhibitors are furthest in development as discussed in Chaps. 2-4 (De and Migliaccio 2005 Manns et al. 2007 Pawlotsky et al. 2007). 

Table 2 Mutations associated with resistance to HCV NS5B polymerase inhibitors in vitro (Lin et al. 2007 Manns et al. 2007)...

Howe AY, Cheng H, Thompson I, Chunduru SK, Herrmann S, O Connell J, Agarwal A, Chopra R, Del Vecchio AM (2006) Molecular mechanism of a thumb domain hepatitis C virus nonnucleoside RNA-dependent RNA polymerase inhibitor. Antimicrob Agents Chemother 50 4103 113... 

Le PS, Kang H, Harris SF, Leveque V, Giannetti AM, Ali S, Jiang WR, Rajyaguru S, Tavares G, Oshiro C, Hendricks T, Klumpp K, Symons J, Browner ME, Cammack N, Najera I (2006b) Selection and characterization of repUcon variants dually resistant to thumb- and palm-binding nonnucleoside polymerase inhibitors of the hepatitis C virus, J Virol 80 6146-6154... 

Lu L, Dekhtyar T, Masse S, PithawaUa R, Krishnan P, He W, Ng T, Koev G, Stewart K, Larson D, Bosse T, Wagner R, PUot-Matias T, Mo H, MoUa A (2007) Identification and characterization of mutations conferring resistance to an HCV RNA-dependent RNA polymerase inhibitor in vitro. Antiviral Res 76 93-97... 

TMN191 11. NS5B RNA-dependent RNA polymerase inhibitors InterMune/Roche Phase 1... 

HCV NS5B Polymerase Inhibitors in Combination with Interferons... 

HCV-796 is a non-nucleosidic NS5B polymerase inhibitor with potent antiviral activity in vitro. A phase lb study was performed to determine the antiviral activity, pharmacokinetics, and safety of HCV-796 in patients with chronic HCV infection. Maximum antiviral effects were achieved after 4 days of treatment with a mean reduction of HCV-RNA of 1.4 loglOIU/ml. Combination of HCV-796 with pegylated interferon-a led to a greater reduction of viral RNA load (3.3-3.5 loglO lU/ml) after a 14 days treatment interval. 

Ikegashira et al. reported another recent example of the successful exploitation of conformational locks. They describe the discovery of a novel class of hepatitis C virus NS5B RNA polymerase inhibitors [42]. By designing and synthesizing conformationally constrained analogs of 40 (see Fig. 8.9), they obtained a series of novel compounds with significantly improved potency. Compound 41 was, for example, shown to be 7-fold more potent, see Fig. 8.9. 

Structurally related quinoxalines have been identified as sub-micromolar HCV polymerase inhibitors in a high throughput screen (HTS). Derivatives that are unsymmetrically substituted with hydrophobic groups on the pyrazine moiety, and with a pendant hydroxy-tryptophan side-chain that has been reported previously (vide infra), provide the greatest activity (14, IC50 = 0.6 pM) [56]. 

A series of pyranoindole polymerase inhibitors has been disclosed [95,96], and this research was expanded to include benzothienopyrans and... 

Bryant HE and Helleday T (2004) Poly(ADP-ribose) polymerase inhibitors as potential chemotherapeutic agents. Biochem Soc Trans 32 959-961... 

Delaney CA, Wang LZ, Kyle S, White AW, Calvert AH, Curtin NJ, Durkacz BW, Hostomsky Z, Newell DR (2000) Potentiation of temozolomide and topotecan growth inhibition and cytotoxicity by novel poly(adenosine diphosphoribose) polymerase inhibitors in a panel of human tumor cell lines. Clin Cancer Res 6 2860-2867... 

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