Protease viral

Antiviral Drugs Viral Proteases Chemokine Receptors... 

Calpains Viral Proteases Antiviral Drugs Non-viral Peptidases... 

Viral Proteases. Figure 1 Role of virally encoded proteases in the replication cycle of a retrovirus (HIV, part a) and of a (+)-strand RNA virus (HCV, part b). The numbers correspond to the following steps in the infectious cycle ... 

The nonstructural region of the precursor, harboring the viral replication machinery, is cut into its mature components in a maturation reaction in which two viral proteases (NS2-pro and NS3/4A-pro) cooperate. Site-directed mutagenesis of an other wise infectious cDNA has shown that both HCV-encoded proteases are necessary for viral infectivity, but most of the attention has so far been focused on one of them a member of the serine protease family (EC 3.4.21) located in the N-terminal region of the viral NS3 protein. 

Hsu JT, Wang HC, Chen GW et al (2006) Antiviral drug discovery targeting to viral proteases. Curr Pharm Des 12 1301-1314... 

VIPomas Viral Proteases Viral Vectors Virostatics Vitus-like Particle Vitamin A Vitamin B1 Vitamin B2 Vitamin B6 Vitamin B12 Vitamin C Vitamin D... 

Abstract This review provides an overview of the development of viral protease inhibitors as antiviral drugs. We concentrate on HlV-1 protease inhibitors, as these have made the most significant advances in the recent past. Thus, we discuss the biochemistry of HlV-1 protease, inhibitor development, clinical use of inhibitors, and evolution of resistance. Since many different viruses encode essential proteases, it is possible to envision the development of a potent protease inhibitor for other viruses if the processing site sequence and the catalytic mechanism are known. At this time, interest in developing inhibitors is Umited to viruses that cause chronic disease, viruses that have the potential to cause large-scale epidemics, or viruses that are sufQciently ubiquitous that treating an acute infection would be... 

The requirements of protease inhibitors as drugs in terms of potency, pharmacokinetics, and toxicity will vary depending on the nature of the infection and the goals of therapy. At one extreme is treatment of HlV-1, a chroific infection that requires life-long therapy and full suppression of viral replication. At the other extreme is the treatment of human rhinovirus (i.e., the cold virus), where short-term treatment to blunt viremia will likely be sufficient to reduce the unwanted symptoms of a cold. In all cases, viral proteases represent very attractive targets with familiar mechanisms of catalysis that frequently allow for the design of transition state analogs and with distinct specificities from host proteases. 

Rhinovirus, like poliovirus, synthesizes a large precursor protein from which all of the mature viral proteins are generated. Two viral proteases are involved in these cleavages 2A protease cleaves the polyprotein precursor at its own N terminus, while the 3C protease is responsible for additional cleavage events to generate the mature viral proteins. Both proteases can release themselves from the polyprotein precursor. Cleavage by 3C occurs between Gln/Gly, but flanking sequences affect efficiency (reviewed in Racaniello 2001). 

Acknowledgments We thank NIH for funding (grants ROl GM65347 and POl GM66524) of the Swanstrom and Schiffer laboratories in the area of viral protease research. Keith Romano and Madhavi Nalam provided assistance with the features. We also thank Leslie Arney and Catherine W. Deschapelles for critical review of the manuscript. 

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