Peptide, SAR

Structural information and computational methods have considerable potential in supporting the transformation of bioactive peptides into small molecules. Of major importance is combining all available information on the system of interest, including peptide SAR data, information on the consequences of mutations in the target on SAR, structural information from both the target protein and related proteins as well as the particular ligand and all other known ligands. 

Peptide SAR studies resulted in potent bradykinin Bj receptor antagonists like HOE 140 D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg. Replacement of some of the amino acids by substituted 1,3,8-triazaspiro[4,5]decan-4-one-3-acetic acids in the B2 receptor antagonist D-Arg-Arg-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg gave potent B2 receptor antagonists like compound 82 (NPC 18521, 0-15 nM) which contains a... 

Sticht J, Humbert M, Findlow S, Bodem J, Muller B, Dietrich U, Werner J, Krausslich HG (2005) A peptide inhibitor of HIV-1 assembly in vitro. Nat Struct Mol Biol 12 671-677 Stockman LJ, Bellamy R, Garner P (2006) SARS systematic review of treatment effects. PLoS... 

Lee TW, Chemey MM, Huitema C, Liu J, James KE, Powers JC, Eltis LD, James MN (2005) Crystal structures of the main peptidase from the SARS coronavirus inhibited by a substrate-fike aza-peptide epoxide. J Mol Biol 353 1137-1151 Liang PH (2006) Characterization and inhibition of SARS-coronavirus main protease. Curr Top Med Chem 6 361-376... 

Attaching some short peptidic sequences to adamantane makes it possible to design novel antagonists. The bradykinin antagonist, which is used as an anticancer agent, is an example. The adamantane-based peptidic bradykinin analog was utilized in strucmre-activity relationship (SAR) studies on the bradykinin receptors and showed a potent activity in inhibition of bradykinin-induced cytokine release and stimulation of histamine release [142]. 

DESIGN AND SAR OF PEPTIDE DEFORMYLASE INHIBITORS Early Substrate-based Inhibitors... 

This article summarises the general characteristics of a novel antibacterial target, peptide deformylase (PDF) and reviews the design, structure-activity relationships (SAR) and properties of known PDF inhibitors, including pre-clinical and clinical data for the most advanced members of this class. 

The first non-peptide oxytocin antagonists, based on a spiropiperidine template, were described by Merck in 1992 [68-70]. The binding affinity data for key compounds from this series are summarised in Table 7.2. The initial screening hit, L-342,643, (23), had modest (4/iM) affinity for rat uterine oxytocin receptors and very little vasopressin selectivity [71]. A structure activity relationship (SAR) study was carried out around this template, focussing on the toluenesulphonamide group. This work led to the identification of bulky lipophilic substitution as key to improved oxytocin potency, while the introduction of a carboxylic acid group led to improved... 

The discovery of inhibitors of fibrillogenesis has been hampered by the complexity of the folding pathway, the presence of mixed populations of aggregates, and the lack of sensitive markers of each oligomeric species.40 Screening assays based on thioflavin-S fluorescence or Congo-red absorbance have been used to identify inhibitors of aggregation of synthetic Af peptide. The reported compounds suffer from relatively low potency (effective at <10 pM) and "flat" SARs." 43... 

The classic endogenous opioid peptides are derived from one of three families of precursors proopiomelanocortin (POMC), pro-dynorphin, and pro-enkephalin. Many active opioid peptides are derived from these three, but the best known are )S-endorphin, enkephalin, and dynorphin. POMC is produced by nuclei in the hypothalamus and medulla (Khachaturian et al. 1985 Watson et al. 1978 Bloom et al. 1978). Enkephalin and dynorphin neurons are distributed to all levels of the central nervous system (Hokfelt et al. 1977 Khachaturian et al. 1983 Sar et al. 1978 Khachaturian et al. 1985). 

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