Antiviral enzyme inhibitors

In the host cell, viruses induce the formation of enzymes that they themselves cannot produce. The most important group of such enzymes is that of the DNA polymerases, but thymidine kinase is also essential. Interference with these enzymes by either enzyme inhibitors or through fraudulent antimetabolites is the basis of the activity of many antiviral drugs. In this respect, antiviral compounds and cytostatics used in the treatment of malignant tumors have much in common and indeed overlap each other in their activity. 

Human PepTl was initially cloned from intestine (92) and was found to be localized to the brush border of intestinal epithelial cells (93) and in SI segment of apical proximal tubules (94). PepTl transports (3-lactam antibiotics (95), antiviral drugs such as valacyclovir and valganciclovir (96), and the angiotensin converting enzyme inhibitor captopril (97). Polymorphisms have been reported, however little is known regarding their functional consequences (64). 

Volume 43 Natural Products Isolation. Separation Methods for Antimicrobials, Antivirals and Enzyme Inhibitors edited by G.H. Wagman and R. Cooper... 

The phosphonic amino acids are also an important class of compounds with applications as antibiotics, antiviral agents, and enzyme inhibitors. The first example of electrophilic amination of a-cuprophosphonates 14 was reported by Genet and co-workers [5a]. This route has opened new access to N-protected a-amino phosphonic derivates 15 from the corresponding phosphonates 13 (Scheme 5). 

As an example, we can consider the discovery and development of an antiviral drug. Inhibitors of the HIV protease, an enzyme essential for the maturation of the virus, can potentially cure HIV-infected people. The discovery process may consist of finding samples able to inhibit the viral aspartic protease over a certain threshold, while having little or no effect on another protease of the same class, such as pepsin. The hits will be submitted to further biological tests to identify leads, patentable compounds that are capable, for example, of inhibiting viral replication in cellular models. 

The sites at which anti-HIV drugs may. in principle, act, are dealt with in detail under a main heading (see ANTIVIRAL agents). In summary, currently, of the drugs actually in use, a number are reverse transcriptase (enzyme) inhibitors (RTIs). Examples of nucleoside RTIs include zidovudine, didanosine and zalcitabine. Some non-nucleoside RTIs include foscarnet sodium, nevirapine, carbovir and TIBO analogues (some of these are at trial stage only). 

Another nucleoside-derived mechanism-based enzyme inhibitor is Fluoronepla-nocin A [79]. This compound is of interest as a broad-spectrum antiviral drug which acts by irreversible inhibition of S-adenosylhomocystein hydrolase (SAH). In a first enzymatic reaction step the 3 -hydroxy group of the inhibitor is oxidized to the corresponding ketone (Scheme 4.34). This leads to depletion of the biochemical oxidizer nicotinamide adenine dinudeotide (NAD ). In the next step a nucleophilic residue of the enzyme undergoes Michael addition to the /i-fluoro a,/>-unsatu-rated ketone moiety. This is followed by fluoride elimination and thus the inhibitor stays covalently trapped in the active site and disables the enzyme permanently. 

Heterocycle-fused acridines possess a variety of biological activities, including Ca releasing, antiviral (e.g., anti-HIV), antimicrobial (e.g., anti-amebic and antiplasmodium) and antitumor properties. They are also enzyme inhibitors (e.g., topoisomerase II inhibitors and protein tyrosine kinase inhibitors) and have DNA-intercalation and metal-chelating properties. 

As a final note, there is the observation that antiviral agents act to inhibit the replication of nucleic acids. There is a connection with anticancer agents, which are enzyme inhibitors for DNA processes. In a way, the connection is obvious, in view of the fact that viruses are but pieces of DNA. A search of Medline indicates that antiviral agents being cUnically tested include inhibitors for the enzymes called nucleoside phosphorylases and M-deoxyribosylttansferases. 

The antiviral antibiotic limocrocin (61) is the pigment produced by Streptomyces limosus [123a] an enzyme inhibitor agams reverse transcriptase [123b]. This is a symmetrical diamide derived from... 

Wagman, G. H. and Cooper, R. (eds.) (1989) Natural Products Isolation. Separation Methodsfor Antimicrobials, Antiviral and Enzyme Inhibitors, Journal of Chromatography Library, vol. 43. Elsevier, Amsterdam. 

The products of the phospho-aldol reaction, a-functionalised phosphonate esters such as a-hydroxy- and a-aminophosphonates, find widespread application directly or indirectly as precursors to enzyme inhibitors (such as the enzymes renin [6], thrombin [7],EPSP synthase [8], HIV protease [9] and various classes of PTK and PTPs [10]) and phosphate analogues [11], antibiotics [ 12], antiviral agents [ 13], and in nucleotide technology [ 14]. Within each application stereochemistry of the phosphonate is crucial to eliciting the required properties [15]. 

Several biobased surfactants have been reported to have manifold biological activities covering antibiotics, fungicidal, insecticide, antiviral and antitumoral agents, immunomodulators or specific toxins, and enzyme inhibitors [30]. 

Examples of pharmaceutically useful groups include hydrophUic-ity and hydrophobicity modifiers, pharmacokinetic modifiers, antigens, receptor ligands, nucleotides, chemotherapeutic agents, antibacterial agents, antiviral agents, immimomodulators, hormones and their analogs, enzymes, inhibitors, alkaloids, and therapeutic radionuclides. 

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