β‐Amino Acid‐Containing Hybrid Peptides — New Opportunities in Peptidomimetics.

Aguilar, Marie‐Isabel; Purcell, Anthony W.; Devi, Romila; Lew, Rebecca A.; Rossjohn, Jamie; Smith, A. Ian; Perlmutter, Patrick

doi:10.1002/chin.200749275

Cited by 5 publications

(5 citation statements)

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“…As they are isomers of the proteinogenic amino acids, they are especially useful as building blocks for therapeutic polymers mimicking peptide-peptide interactions, which display promising bioavailability and in vivo stability when compared to natural proteins. [250][251][252] Derivatives of these chemicals with aromatic side chains are also used in the synthesis of small molecule pharmaceuticals, as well as being found in bioactive natural products (Scheme 37). Although the use of β-amino acids seems to be less widespread than that of the α-isomers, it is unclear whether this is due to lack of focus on asymmetric methods to provide amenable routes to these compounds.…”

Section: Synthesis Of β-Arylalaninesmentioning

confidence: 99%

Synthetic and Therapeutic Applications of Ammonia-lyases and Aminomutases

et al. 2017

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Ammonia-lyases and aminomutases are mechanistically and structurally diverse enzymes which catalyze the deamination and/or isomerization of amino acids in nature by cleaving or shifting a C-N bond. Of the many protein families in which these enzyme activities are found, only a subset have been employed in the synthesis of optically pure fine chemicals or in medical applications. This review covers the natural diversity of these enzymes, highlighting particular enzyme classes that are used within industrial and medical biotechnology. These highlights detail the discovery and mechanistic investigations of these commercially relevant enzymes, along with comparisons of their various applications as stand-alone catalysts, components of artificial biosynthetic pathways and biocatalytic or chemoenzymatic cascades, and therapeutic tools for the potential treatment of various pathologies.

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Section: Synthesis Of β-Arylalaninesmentioning

confidence: 99%

Synthetic and Therapeutic Applications of Ammonia-lyases and Aminomutases

et al. 2017

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“…C 3 -b-amino acid substitution introduces an amino acid with a similar side chain but containing an additional methylene group (CH 2 ) in the peptide backbone between the a carbon (aC) and the carbonyl carbon (C --O). This substitution can greatly affect the binding properties and stability of the b-analog peptides (Steer et al, 2002;Webb et al, 2005;Aguilar et al, 2007;Seebach and Gardiner, 2008) through changes to backbone conformation, relayed structural effects or non-structural changes to the spatial positioning of the side chains due to the inclusion of a b-amino acid in the peptide backbone. Our data shows that dramatic structural changes occur when b-amino acids are introduced into AngII, with CD spectra showing a diverse variety of structures for the different b-analogs.…”

Section: Introductionmentioning

confidence: 99%

β‐amino acid substitution to investigate the recognition of angiotensin II (AngII) by angiotensin converting enzyme 2 (ACE2)

Clayton

Hanchapola

Hausler

et al. 2011

J of Molecular Recognition

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In spite of the important role of angiotensin converting enzyme 2 (ACE2) in the cardiovascular system, little is known about the substrate structural requirements of the AngII-ACE2 interaction. Here we investigate how changes in angiotensin II (AngII) structure affect binding and cleavage by ACE2. A series of C3 β-amino acid AngII analogs were generated and their secondary structure, ACE2 inhibition, and proteolytic stability assessed by circular dichroism (CD), quenched fluorescence substrate (QFS) assay, and LC-MS analysis, respectively. The β-amino acid-substituted AngII analogs showed differences in secondary structure, ACE2 binding and proteolytic stability. In particular, three different subsets of structure-activity profiles were observed corresponding to substitutions in the N-terminus, the central region and the C-terminal region of AngII. The results show that β-substitution can dramatically alter the structure of AngII and changes in structure correlated with ACE2 inhibition and/or substrate cleavage. β-amino acid substitution in the N-terminal region of AngII caused little change in structure or substrate cleavage, while substitution in the central region of AngII lead to increased β-turn structure and enhanced substrate cleavage. β-amino acid substitution in the C-terminal region significantly diminished both secondary structure and proteolytic processing by ACE2. The β-AngII analogs with enhanced or decreased proteolytic stability have potential application for therapeutic intervention in cardiovascular disease.

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“…Formation of C-terminal enamides by Porco et al 127 A related decarboxylation strategy was used to obtain peptide hybrids, such as -peptides, which can present new folding patterns, depending on the  ratio and distribution. 128,129 In addition, they usually display superior resistance to proteases and hence, in vivo stability. Boto et al described the synthesis of -tripeptides where the central unit was a disustituted -aminoacid (conversion 187→189/190, Scheme 46).…”

Section: Selective Conversion Of C-terminal Unitsmentioning

confidence: 99%