Viruses discovery

Sarrazin, C., Roth, W.K., Zenzem, S. Heterosexual transmission of GB virus-C / hepatitis G virus infection. Eur. X Gastroenterol. Hepatol. 1997 9 1117—1120 GB virus C / hepatitis G virus discovery. 

Some of the pioneering studies of adenovirus infection performed during the decade following the virus discovery elucidated the general properties of the response of permissive cells to adenovirus infection as descriptions in morphological terms were rapidly succeeded by investigations of alterations in macromolecular synthesis. 

The original Central Dogma of molecular biology (left) and its modification in light of the discovery of viruses (right). 

Baltimore D (1971) Expression of animal virus genomes. Bacteriol Rev 35 235-241 Baltimore D (1988) Gene therapy. Intracellular immunization. Nature 335 395-396 Bauer DJ (1985) A history of the discovery and clinical application of antiviral drugs. Br Med Bull... 

Crystal structures of the NS5B polymerase alone and in complexes with nucleotide substrates have been solved and applied to discovery programs (Ago et al. 1999 Bressanelli et al. 2002 Bressanelli et al. 1999 Lesburg et al. 1999 O Farrell et al. 2003). From these studies, HCV polymerase reveals a three-dimensional structure that resembles aright hand with characteristic fingers, palm, and thumb domain, similar to the architectures of the RNA polymerases of other viruses. However, none of these experimental structures contained the ternary initiation complex with nu-cleotide/primer/template, as obtained with HIV RT. Accordingly, HCV initiation models have been built using data from other viral systems in efforts to explain SAR (Kozlov et al. 2006 Yan et al. 2007). 

Wu JZ, Yao N, Walker M, Hong Z (2005) Recent advances in discovery and development of promising therapeutics against hepatitis C virus NS5B RNA-dependent RNA polymerase. Mini Rev Med Chem 5 1103-1112... 

An overview of the role of the virus-associated glycoprotein sialidase (neuraminidase) and some of the most recent developments towards the discovery of anti-influenza drugs based on the inhibition of influenza virus sialidase is provided in this chapter. 

As a result of the emergence of the extremely aggressive avian H5N1 influenza virus, the likelihood of a human influenza pandemic and the possible socioeconomic impact is now of major concern. In the absence of strain-independent anti-influenza drugs, there has been significant effort worldwide over the years in the quest for the discovery of novel therapeutic agents against all types of influenza. 

The discovery of the potent in vitro sialidase inhibitory activity and in vivo efficacy of zanamivir 12, and the increasing availability of 3D structural data for influenza virus sialidases in the 1990s, particularly with Neu5Ac and various inhibitors bound into the active site, provided a platform for further drug discovery efforts targeting... 

Smith PW, Sollis SL, Howes PD, Cherry PC, Starkey ID, Cobley KN, Weston H, Scicinski J, Merritt A, Whittington A, Wyatt P, Taylor N, Green D, BetheU R, Madar S, Fenton RJ, Motley PJ, Pateman T, Beresford A (1998) Dihydropyrancarboxamides related to zanamivir a new series of inhibitors of influenza virus sialidases. 1. Discovery, synthesis, biological activity, and structure-activity relationships of 4-guanidino- and 4-amino H-pyran-6-carboxamides. J Med Chem 41 787-797... 

Abstract In 2007, the world celebrated the 50th anniversary of the discovery of interferon (IFN) by Isaacs and Lindemnann. Subsequently, the IFN-a gene was cloned, fully sequenced and IFN-a was produced in recombinant form. Recombinant IFN-a is now used as the basis for treatment of chronic hepatitis C virus infection and can also be used to treat certain forms of chronic hepatitis B virus infections. IFNs have also been used in other viral infections, although with less success. The antiviral mechanisms of IFNs are reviewed in this chapter as well as the utility of IFNs in the treatment of persistent viral infections. 

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. 

Noji, S., Yamanaka, H., Hara, Y., Adachi, T., Tsuruha, J. I., Doi, S., Hase, Y., Noguchi, T., Ando, I., Ogura, N., Ikeda, S., Hashimoto, H. Discovery of conformationally constrained tetracyclic compounds as potent hepatitis G virus NS5B RNApolymerase inhibitors./. Med. Chem. 2006, 49, 6950-6953. 

Once potent ligands for a viral protein are identified, further advancement depends on demonstrating activity in cells. Unfortunately, reproducible in vitro viral replication assays for HCV have not been reported. There are scattered reports that a very low level of genome replication, or even virus production, can be observed under certain circumstances [56]. However, recently specific sequences yielding relatively reproducible replication, at consistently detectable levels have been reported [57]. In the coming years these may allow routine assays suitable for compound evaluation to be developed, but to date drug discovery must rely on other cell culture models. 

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