Antiviral compounds peptides

Peptide a-oxo acids, a-oxo esters, and a-oxoamides are also potent inhibitors of cysteine and serine proteases. Oxidation of peptide a-substituted carboxylic acid derivatives provides a general route to these compounds (Section 15.1.5). Peptide hydroxamic acids have been shown to be inhibitors of metalloproteinase and some have been reported to have antibiotic, anticarcinogenic, and antiviral activities. Peptide hydroxamic adds may be prepared by solution and solid-phase methods using a variety of resins (Section 15.1.6). a-Aminoboronic acids may be prepared by several routes and are reported to be inhibitors of aminopepti-dases. Procedures have been developed for their incorporation into peptides (Section 15.1.7). 

Abstract Infectious diseases cause severe problems in the aquaculture industry, with viral diseases being responsible for the greatest losses in production. Disease prevention strategies still have some limitations in terms of safety and efficacy. Antimicrobial peptides (AMPs) are molecules of the innate immune system, one of the first lines of defense against pathogens. Usually they not only exhibit antimicrobial activity, but also modulate the immune response. This review focuses on fish AMPs and their antiviral and immunoregulatory activities in order to assess their potential relevance to aquaculture. Since fish depend on their innate immune defenses more than mammals, they could be an alternative source of novel antiviral compounds. 

Other potent peptide mimetic NS3 protease inhibitors have been reported that incorporate a serine trap on the C-terminal end of the peptide. Thus, the inhibitory activity of telaprevir (VX-950, 59), (7nM vs. NS3, 300 nM vs. the la replicon) is based on truncation of the polypeptide substrate, maximizing binding by alteration of amino acids at the scissile site, and capping both N- and C-terminal ends, the latter with a known dicarbonyl serine trap. This compound has exhibited impressive antiviral activity in animals, and showed a 4.4 log drop in viral load in genotype 1-infected patients in a Phase lb clinical trial [110]. Telaprevir is expected to enter Phase 3 clinical trials in 2007. Additional bicyclo-proline-based P2 tetrapeptides, represented by analog 60 (Kj = 22 nM), have been explored. Although the compounds are selective inhibitors of NS3, little or no cell-based replicon activity was reported, presumably due to poor cellular permeability [111-114], A diastereomer of telaprevir, has been reported to inhibit the replicon with an EC50 of 0.55 pM [115]. 

An antiviral (and anticancer) compound very much in the news media is interferon, a peptide consisting of about 150 amino acids (discussed in chapter 6). It is produced by most cells upon viral infection or a challenge by interferon-inducing agents, and protects... 

Despite two peptide bonds present in ABT-538, this compound has substantial oral availability in humans and a very high antiviral activity in vivo [30]. Recently, ABT-538, better known as ritonavir, has been approved by the FDA for treatment of AIDS in combination with inhibitors of the reverse transcriptase. 

Mass screening of our compound collection, utilizing the Amersham SPA technology, afforded pyrone and coumarin non-peptide templates as initial lead structures. X-ray cocrystallization and structure-based design were utilized to assist in the design of more potent inhibitors. These efforts resulted in the design of the 5,6-dihydropyrones, which afforded a more flexible template from which to fill the internal pockets of the enzyme. Optimization of the dihydropyrone series afforded a potent antiviral agent,... 

The inhibitory effects of the pyrrolinone derivatives were evaluated using enzyme inhibition and cellular activation assays. Compound 6 (Fig. 4.3-5) showed an IC50 of 10 nM, compared to 0.6 nM for the related peptide inhibitor 5 (L682,679). However, the synthetic agent 6 showed better cell transport capacity. In a cellular antiviral assay, 5 and 6 showed CIC95 values (the concentration that inhibits 95% of virus multiplication in the cellular cultures) of 6.0 and 1.5 pM, respectively. Smith and Hirschmann proposed that the improved cellular uptake properties of polypyrrolinones are due to a reduction in the inhibitor solvation. Solvation is an impediment to transport because extraction of a molecule into a lipid bilayer from an aqueous phase is... 

Table 10. Antiviral Marine-Derived Peptides, Alkaloids, Proteins, Nucleosides and Other A -Containing Compounds...

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