Virus inactivation inhibitors

Koudriakova T, latsimirskaia E, Utkin I, et al. Metabolism of the human immunodeficiency virus protease inhibitors indinavir and ritonavir by human intestinal microsomes and expressed cytochrome P4503A4/3A5 mechanism-based inactivation of cytochrome P4503A by ritonavir. Drug Metab Dispos 1998 26(6) 552-561. 

Chiba, M. Nishime, J.A. Lin, J.H. Potent and selective inactivation of human liver microsomal cytochrome P-450 isoforms by L-754,394, an investigationed human immune deficiency virus protease inhibitor. J.Pharmacol.Exp.Ther., 1995, 275, 1527—1534... 

Extracts from 152 plant species, representing 46 different families, were screened for effects on tobacco mosaic virus (TMV) replication in cucumber cotyledons. Twenty species have shown enough activity to warrant further study. Several members of the Caprifoliaceae family increased virus replication. An extract of Lonicera involucrata enlarged the virus lesions in local lesion hosts and produced a thirty fold increase in virus titer, but had no effect on virus replication in systemic hosts. The active material appears to affect the virus defense mechanism of local lesion hosts. An extract of common geranium is an active virus inhibitor. It inactivates TMV and TMV-RNA (ribonucleic acid) in vitro by forming non-infectious complexes. In vivo, it also inhibited starch lesion formation in cucumber cotyledons incited by TMV infection. 

Tannic acid is a strong inhibitor of virus particles in vitro. It inactivated both TMV and TMV-RNA by forming noninfectious complexes (1). TMV-RNA was much more sensitive to inactivation than was whole TMV. It would thus appear that tannic acid could possibly inactivate TMV by reacting with either the protein coat or the RNA core. 

Fig. 1 Antiviral genes inhibit virus replication at different stages of the viral life cycle. Early inhibitors prevent the establishment of the viral genome in the target cell (class I, e.g., entry inhibitors, RT inhibitors for HIV). Intermediate inhibitors prevent viral gene expression or amplification of the viral genome (class II, e.g., siRNAs, antisense RNAs). Late inhibitors prevent virion assembly or release, or inactivate the mature virions (class III, e.g., transdominant core proteins, capsid-targeted virion inactivation, CTVI). A list of antiviral genes in each class is found in Table 1...

It has proven extraordinarily difficult to obtain an inhibitor of sufficient potency (15), bioavailability, and safety to be used in the clinic. The ability of HIV to mutate, and thus to develop resistance to many inhibitors, is an additional hurdle. In spite of the difficulties, chemists persisted, motivated by the knowledge that inactivating this HIV-encoded enzyme inactives the virus. Their efforts have provided HTV protease inhibitors that are being evaluated for clinical efficacy (16). 

Acyclovir (ACV) is not a true nucleoside, because the guanine residue is attached to an open-chain structure, but it mimics deoxyribose well enough for the compound to be accepted as a substrate by a thymidine kinase specified by certain herpes-type viruses. The normal thymidine kinase in mammalian cells does not recognize ACV as a substrate, however, so only virus-infected cells convert ACV to its monophosphate. Once the first phosphate has been added, the second phosphate is added by cellular guanylate kinase several other cellular kinases can add the third phosphate. The triphosphate is a more potent inhibitor of the viral DNA polymerases than of cellular DNA polymerases and also inactivates the former but not the latter. The net result is that ACV has been an effective treatment of, and prophylaxis for, genital herpes. Also it can result in dramatic relief of pain associated with shingles caused by reactivation of latent varicella-zoster virus, and has been successful in many patients with herpes encephalitis. 

Apart from lAPs, there are several nonmammalian regulators of caspases, which are active-site specific inhibitors (Callus and Vaux, 2007). One example is a serpin from the cowpox virus, cytokine response modifier A (crmA). CrmA forms a covalent complex with the initiator caspase-1 and -8 resulting in irreversible inhibition of these caspases. It also inhibits caspase-6 but less efficiently (Dobo et al., 2006). The baculoviral protein p35 is a broad spectrum caspase inhibitor that irreversibly inactivates caspases (Bump et al., 1995 Fisher et al., 1999). 

Chemical inhibitors of proteases may be used to Inactivate the participating enz5nnes. lodoacetamlde and iodoacetate >prevent processing of virus proteins. Dlisopropyl fluorophosphate, probably acting as an inhibitor of a serine active-site protease, also prevents the processing of poliovirus polyprotein. Finally, chloromethyl ketones of selected amino acids, particularly that of phenylalanine, have been widely used in successful tests to block viral protein processing. The... 

---