Peptidic macrocycles inhibitors

Two non-peptidic macrocyclic inhibitors of the ETa receptor have also been described. The bromotyrosine-derived macrolactam 34-sulfatobastadin 13 (33, Figure 8.13), isolated from the sponge lanthella sp., weakly inhibits the binding of [ I]-ET-1 to the ETa receptor with an IC50 of 39 pM. The polyketide (—)-kendomycin (34, TAN-2162, Figure 8.13) is a moderately potent inhibitor of both endothelin receptors (ETa IC5o = 11.5 pM ETb ICso = 2.9 pM), isolated from Streptomyces sp AL-71389. ... 

Figure 16 (a) Structures of adenylation domain intermediates and inhibitors aminoacyl-sulfamoyl adenosine (AMS) and cisoid -like macrocyclic inhibitor, (b) Alkyne-functionalized chemical probe for NRPS A and PCP domains, (c) Structure of aminoacyl PCP, SNAC substrate analogue, and hydrolytically stable phosphopantetheinyl analogue, (d) Structure of vinylsulfonamide probe. R represents a peptide component and R an amino acid side chain. 

R. A. Smith, P. J. Coles, J. J. Chen, V. J. Robinson, I. D. MacDonald, J. Carriere, and A. Krantz, Bioorg. Med. Chem. Lett., 4, 2217 (1994). Design, Synthesis and Activity of Conformationally Constrained Macrocyclic Peptide-Based Inhibitors of HIV Protease. 

A series of peptidic macrocycles has been published by researehers from Harvard and Stony Brook University who reported highly specific, bisubstrate-competitive proto-oncogene tyrosine protein kinase Src inhibitors... 

In order to minimize peptide-like properties, macrocycles have been incorporated into these protease inhibitors. For example, connecting the P2 aryl side and P3 capping group gives 63, a 160 nM inhibitor (Kj) [121]. The optimal 17-membered macrocycle reportedly enhanced binding with NS3 by forming an... 

Several potent inhibitors of fibrinogen binding to gpIIb/IIIa are now known, and some have proven to be effective antithrombotic agents. These inhibitors tend either to be small cyclic peptide mimetics, in which the conformation of an RGD sequence is constrained by macrocyclization, or they are non-peptidic molecules containing functional group mimetics of the Arg and Asp side chains, held in the correct geometry for interaction with the receptor. Examples of both classes are shown in... 

Previous reviews on peptidomimetics have addressed pseudopeptides (11), macrocyclic mimetics (13), natural product mimetics (14), cyclic protease inhibitors (15), mimetics for receptor ligands (16-22), and earlier general overviews (23-29). This review will focus on the design process itself. Novel peptidomimetics in which the structural relationship between parent peptide and the peptidomimetic has been established by biophysical methods are used to clarify the principles. Successful approaches are highlighted to illustrate how these concepts are currently used. 

Macrocyclic peptides, inhibitors of serine proteases, as potential therapeutic agents 04JMC769. 

Thiopeptide antibiotics, thiazolyl peptides, naturally occurring sulfur-containing, highly modified, macrocyclic peptides. They share a number of structural motifs, including several heterocycles such as thiazoles, a dehydropiperidine, a pyridine, oxazoles, and indoles. Nearly aU of the thiopeptide antibiotics act as inhibitors of protein synthesis in bacteria. They are secondary metabolites produced by actino-mycetes, largely by the genus Streptomyces. A representative member of this family is thiostrepton [M. C. Bagleyetal., Chem. Rev. 2005, 105, 685]. 

Niche for acridine derivatives in anticancer therapy 13MRM1256. Peptide based macrocycles Selective histone deacetylase inhibitors with antiproliferative activity 13CMD1887. 

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