Antiviral compounds proteins

Since the pioneering work of Kleymann et al. (2002), Betz et al. (2002), Baumeister et al. (2007), and Crute et al. (2002), who showed that compounds identified as inhibitors of the helicase-primase enzyme complex could alleviate herpesvirus-induced disease in animal models, the attention of researchers developing antiviral compounds has been drawn more and more towards the virus-encoded helicases, particularly those of Herpes viruses and of RNA viruses such as Hepatitis C Virus (HCV) and SAKS coronavirus (SARS-CoV). Enzyme activity is usually assayed by measuring NTPase activity in the presence of an appropriate nucleic acid co-substrate although, more recently, novel fiuorimetric and luminescence principles have been applied to the measurement of strand unwinding and/or translocation of the protein along the nucleic acid (Frick 2003, 2006). 

Virus maturation and assembly at the cell membrane or the nuclear membrane has long been seen as a potential target for antiviral compounds. For the virus to mature and be released in a conformation that will insure stability and survival of the viral genome in the exttacellular enviromnent, the protein subunits of the capsid or nucle-ocapsids have to be transported to the assembly point where they will form the final particles around the viral nucleic acid. If this process does not occur in an orderly and programmed manner, the capsid subunits will not form the required multimers and the viral components will become targets for the cellular disposal mechanisms. 

Figure 11. Human rhinovirus 14 complexed with antiviral compound WIN 52084 (2c). The molecular surface of the protein binding site is color-coded by hydrophobicity as in Figure 2 and the bonds are color-coded by atom type carbon = white, nitrogen = blue, oxygen = red, sulfur = yellow.

Historically, methisazone was one of the first antiviral compounds used in clinical practice. Methisazone (60) acts by interfering with the translation of mRNA message at the ribosome, preventing protein synthesis. Ultimately, it produced a defect in protein incorporation into the virus. Although viral DMA increases and host cells are damaged, an infectious virus is not produced. Methisazone displayed activity against poxviruses, including variola and vaccinia (61). Some RNA viruses, such as rhinoviruses, echoviruses, reoviruses, influenza, parainfluenza, and polioviruses, also were inhibited. Methisazone is not available in the United States and appears to have minimal usefulness today. 

Thiosemicarba2ones have long been used as antiviral agents, principally against pox vimses of the vaccinia family. One compound of this series, the isatin derivative (6) C HgN OS, has been used prophylacticaHy to prevent outbreaks of smallpox in humans (10) and to inhibit the protein synthesis in poxvims-infected cells. The molecular mechanics relating to this property are still not known (11), though the binding of a metal ion may be a key factor... 

In this context, it should be noted that the specific antiviral activity of ganciclovir against HSV (which is more potent than that of acyclovir) can be fully explained by the compound being specifically recognized as substrate by the HSV-encoded TK. For CMV, however, which does not encode a virus-specified TK, the activity of ganciclovir depends on the phosphorylation by a vims-encoded protein kinase, which... 

---