Cyclic peptide inhibitors

Cyclic peptide inhibitors of VLA-1 and fibronectin/vascular cell adhesion molecule... 

Dutta AS, Gormley JJ, Coath M, et al. Potent cyclic peptide inhibitors of VLA-4 (a4 pi Integrin)-mediated cell adhesion. Discovery of compounds like cyclo(MePhe-Leu-Asp-Val-D-Arg-D-Arg) (ZD7349) compatible with depot formulation. 7 Pept Sci 2000 6 398-412. 

Haworth D, Rees A, Dutta AS, et al. Antiinflammatory activity of c(ILDV-NH(CH2)5CO), a novel, selective, cyclic peptide inhibitor of VLA-4-mediated cell adhesion. Br J Pharmacol 1999 126 1751-60. 

Eptifibatide Eptifibatide (integrilin) is a cyclic peptide inhibitor of the fibrinogen binding site on The drug blocks platelet aggregation in vitro after intravenous infusion. Eptifibatide... 

This compound is a cyclic, non-natural peptide with a thiolactone unit and a representative of the group of cyclic peptide inhibitors of staphylococcal virulence. Thiolactone peptides are expected to act as anti-bacterial therapeutics by a highly specific mechanism, as outlined in the following sections. 

As mentioned in the introduction to this chapter, the recent discovery of thiolactone peptides as potential antimicrobial agents, based on flieir ability to act as antagonists of natural auto-inducing peptides (AIP), prompted the new synthetic achievements, which permitted the synthesis of these cyclic peptide inhibitors. Here, we discuss the most recent achievement in the synthesis of AIP mimics, based on an original linker for the Fmoc-based solid-phase methodology. 

Further, Wasserman and coworkers developed a direct acylation of stabilized phosphonium ylides by carboxylic acids in presence of the EDCI/DMAP (way c). This last method allows the introduction of a-aminoacid structures into the resulting P-oxo phosphorus ylides [19-25],opening the way to the total synthesis of depsipeptide elastase inhibitors [22,24] or cyclic peptidic protease inhibitor EurystatinA [20]. 

A different approach toward cyclic peptides has been presented by Leatherbarrow and coworkers, employing ring-dosing metathesis (RCM) on a solid support [50], The authors reported on the synthesis of conformationally strained cyclic peptides of the Bowman-Birk inhibitor type, which are naturally occurring serine protease... 

The peptides discussed so far are defined by a common genetic pattern or architectural feature, such as their sequence or disulfide bond pattern. In this section we discuss peptides that share a common mode of action but may arise from different peptide families. Proteinase inhibitors (Pis) come in an astounding range of sizes, from the smallest gene-encoded cyclic peptide known to date, sunflower trypsin inhibitor 1 (SFTI-1), ° a 14-residue cyclic peptide with a single disulfide bond, to squash inhibitors that are approximately 30 residues in size and feature the cystine knot motif, to 53-residue Pis found in Nicotiana... 

The marine sponge-derived HDAC inhibitors can be classified as cyclic peptides or bicyclic depsipeptides. 

Natural product HDAC inhibitor Helminthosporium carbonum (HC)-toxin (Fig. 14) is produced from filamentous fungus Cochliobolus carbonum Like chlamydocin, this compound is a cyclic peptide that contains both D- and L-amino acids to relieve ring strain. The epoxy group... 

Many other non-peptide inhibitors of HIV protease (dihydropyrone, cyclic urea and sulphamide series of compounds) were obtained by modifications of random screening leads. Examples of these include a cyclic sulph-one derivative 147 and 148 (PNU-140690) that showed activity against a variety of HIV t)rpe 1... 

Non-peptide inhibitors of thrombin (obtained by random screening procedures) include compounds based around benzothiophene (e.g. 155) and other ring systems and cyclic and linear oligocarbamate derivatives (e.g. 156). The benzothiophene derivative 155 showed antithrombotic efficacy in a rat model of thrombosis after infusion (ED50 2.3 mg/kg/h). The cyclic oligocarbamate tetramer 156 inhibited thrombin with an apparent K[ of 31 nM. 

Dutta AS, Crowther M, Gormley JJ, et al. Potent cyclic monomeric and dimeric peptide inhibitors of VLA-4 (a4Pi integrinj-mediated cell adhesion based on the Ile-Leu-Asp-Val tetrapeptide. ] Pept Sci 2000 6 321M1. 

Protein Kinase Inhibitors Pseudosubstrate-based peptide inhibitors, 201, 287 utilization of the inhibitor protein of adenosine cyclic monophosphate-dependent protein kinase, and peptides derived from it, as tools to study adenosine cyclic monophosphate-mediated cellular processes, 201, 304 use of sphingosine as inhibitor of protein kinase C, 201, 316 properties and use of H-series compounds as protein kinase inhibitors, 201, 328 use and specificity of staurosporine, UCN-01, and calphostin C as protein kinase inhibitors, 201, 340 inhibition of protein-tyrosine kinases by tyrphostins, 201, 347 use and specificity of genistein as inhibitor of protein-tyrosine kinases, 201, 362 use and selectivity of herbimycin a as inhibitor of protein-tyrosine kinases,... 

Fig. 6 cyclic peptides as reversible and irreversible HDAC inhibitors. (Chlamydocin San-doz AG CHAP 1 Univ. of Tokyo Apidicin Merck Co reversed hydroxamic acid analogs of Cyl-1 Kyushu Institute of Technology and Japan Science and Technology Agency)... 

The spectral data of the patellamides was also reasssigned and the new assignments used for elucidation of the structures of three new metabolites, the octapeptide prepatellamide B formate (24) and the heptapeptides, prelissoclinamide 2 (25), and preulicyclamide (26) [58]. The molecular conformation of patellamide A (21) was determined by X-ray crystallography [59,60] and the solution conformations of patellamides B (22) and C (23) were determined by NMR spectroscopy and molecular dynamics [61]. The octapeptide preulithiacyclamide (27) is a potent inhibitor of Macrophage Scavenger Receptor and was isolated from L. patella from Palau along with other known cyclic peptides [62],... 

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