Macrocyclic peptidomimetics - Forcing peptides into bioactive conformations

Fairlie D.P., Abenante G. and March D.R. (1995) Macrocyclic peptidomimetics - Forcing peptides into bioactive conformations. Current Medicinal Chemistry, 2 2: 654-686.

Author Fairlie D.P.
Abenante G.
March D.R.
Title Macrocyclic peptidomimetics - Forcing peptides into bioactive conformations
Journal name Current Medicinal Chemistry   Check publisher's open access policy
ISSN 0929-8673
Publication date 1995-01-01
Year available 1995
Sub-type Critical review of research, literature review, critical commentary
Open Access Status Not yet assessed
Volume 2
Issue 2
Start page 654
End page 686
Total pages 33
Place of publication SCHIPHOL
Publisher BENTHAM SCIENCE PUBL BV
Language eng
Subject 1300 Biochemistry, Genetics and Molecular Biology
1303 Specialist Studies in Education
1605 Policy and Administration
3004 Pharmacology
Abstract Cyclic peptides that are potent regulators of biological processes are rapidly emerging as important mechanistic probes and drug leads. Nature clearly uses macrocycles to, constrain peptides into conformations that can selectively bind proteins or small molecules. Therapeutic effects of such macrocycles, often containing additional conformational constraints that fine-tune structure (e.g. D-amino acids, N-methyl substituents, aromatic rings, to name a few), have so far been mainly discovered by accident. However it is now becoming possible to rationally design synthetic macrocycles to selectively recognize and inhibit a specific protein. A receptor-binding structure is more easily adopted by macrocyclic peptidomimetics than more flexible acyclic peptides because the former have less conformational entropy. Macrocycles are often stable to hydrolysis by peptidases that degrade acyclic peptides and hydrophobic side chains can protect peptide bonds in macrocycles from hydrolysis, as well as enhance lipophilicity, cell permeability and bioavailability. Synthetic efforts to obtain bioactive conformations of short peptides have so far been substrate-based, guided by molecular modelling predictions and structure-activity data for modified amino acid sequences of substrates. However, dramatic advances in molecular biology, X-ray crystallography, NMR spectroscopy and computing are rapidly producing three dimensional structures of proteins, promising direct observation of protein-bound conformations of small molecules and receptor-based design of peptidomimetics with surface complementarity for proteins. This perspective review highlights examples of both natural and synthetic bioactive macrocyclic peptides containing constraints that fix conformation, and briefly illustrates the promise that receptor-based design holds for structural and functional mimicry of peptides by macrocycles.
Keyword Biochemistry & Molecular Biology
Chemistry, Medicinal
Pharmacology & Pharmacy
Biochemistry & Molecular Biology
Pharmacology & Pharmacy
BIOCHEMISTRY & MOLECULAR BIOLOGY
CHEMISTRY, MEDICINAL
PHARMACOLOGY & PHARMACY
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Critical review of research, literature review, critical commentary
Collection: Scopus Import - Archived
 
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