Viral proteinases

A. E. Gorbalenya, E. J. Snijder, Viral Cysteine Proteinases , Perspect. Drug Discov. Design 1996, 6, 64-86. 

These drugs are peptidyl analogs that reversibly inhibit the proteinase that is essential for the final step of viral proliferation. Protease inhibitors have revolutionized HIV therapy, reducing infections by opportunistic organisms, and prolonging and improving the lives of most patients. 

The structures of hepatitis A viral 3C proteinases complexed with tetrapeptidyl-based methyl ketone inhibitors were shown to have an episulfide cation embedded in them. The authors concluded that the mechanism of inactivation of 3G peptidases by methyl ketone inhibitors is different than those operating in serine proteinases or in papain-like cysteine peptidases <2006MI673>. 

Interference with assembly of viral coat proteins and viral RNA into new virus particles. Interferons may induce in the ribosomes of the host cells production of enzymes that inhibit translation of viral proteins. Avarol and avarine are thought to interfere with cytoskeletal assembly of virus particles. PROTEASE inhibitors can prevent the release of reverse transcriptase, and HIV-1 proteinase (e.g. saquinavir) are under development or in trial application. 

Among the replicative differences between eukaryotic cells (of the viral host) and the pathogenic virions is that the latter need virus-dependent proteinases to produce the mature infectious virus. That is, HIV protease is an essential enzyme utilized by the virus to process proteins in order to reproduce itself. Retroviruses (and RNA viruses) produce the structural and enzymic proteins as large multidomain polyproteins. The specific cleavage of these various domains into the final products is a posttranslational event. These end-products enable the virion to develop into the actual infectious agent (Kransslich and Wimmer, 1988). 

Standard experiments to determine the method by which schumannificine exerted its effect revealed that it prevented the infection of the host cell by the HIV by binding to the gpl20 on the viral coat. Some glycosidase inhibition was also noted which may contribute to the antiviral effect since this enzyme is important in the formation of new viral material after infection and replication of viral DNA in the host cell [43]. Schumannificine did not possess any reverse transcriptase or proteinase activity. 

Blood samples, including these treated to remove erythrocytes, can be efficiently lysed using lysis buffer and protease or proteinase K. Simultaneously with the human s genomic DNA, viral and bacterial DNA can also be isolated from blood samples. 

Dai E, Guan H, Liu L ct aL Serp-1, a viral anti-inflammatory serpin, emulates cellular serine proteinase and serpin responses to vascular injury. J Biol Chem 2003 278 18563-18572. 

Hausen B, Boeke K, Berry GJ et al. Viral serine proteinase inhibitor (serp-1) effectively decreases the incidence of graft vasculopathy in heterotopic heart allografts. Transplantation 2001 72 364-368... 

---