The cyclic structure of proline (Pro) confers unique conformational properties on this natural amino acid that influences polypeptide structure and function. Pseudoprolines are a family of Pro isosteres that incorporate a heteroatom, most prominently oxygen or sulfur but also silicon and selenium, to replace the C or C carbon atom of the pyrrolidine ring. These readily synthetically accessible structural motifs can facilitate facile molecular editing in a fashion that allows modulation of the amide bond topology of dipeptide elements and influence over ring pucker. While the properties of pseudoprolines have been exploited most prominently in the design of oligopeptide analogues, they have potential application in the design and optimization of small molecules. In this Digest, we summarize the physicochemical properties of pseudoprolines and illustrate their potential in drug discovery by surveying examples of applications in the design of bioactive molecules.
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Proline Analogues.
Chem Rev
July 2024
School of Chemistry, University College Dublin, Belfield, Dublin 4, Ireland.
Within the canonical repertoire of the amino acid involved in protein biogenesis, proline plays a unique role as an amino acid presenting a modified backbone rather than a side-chain. Chemical structures that mimic proline but introduce changes into its specific molecular features are defined as proline analogues. This review article summarizes the existing chemical, physicochemical, and biochemical knowledge about this peculiar family of structures.
View Article and Find Full Text PDFPseudoprolines as stereoelectronically tunable proline isosteres.
Bioorg Med Chem Lett
November 2022
Small Molecule Drug Discovery, Bristol Myers Squibb Research and Early Development, 200 Cambridgepark Drive, Cambridge, MA 02140, USA. Electronic address:
The cyclic structure of proline (Pro) confers unique conformational properties on this natural amino acid that influences polypeptide structure and function. Pseudoprolines are a family of Pro isosteres that incorporate a heteroatom, most prominently oxygen or sulfur but also silicon and selenium, to replace the C or C carbon atom of the pyrrolidine ring. These readily synthetically accessible structural motifs can facilitate facile molecular editing in a fashion that allows modulation of the amide bond topology of dipeptide elements and influence over ring pucker.
View Article and Find Full Text PDFCyclic Tetrapeptides from Nature and Design: A Review of Synthetic Methodologies, Structure, and Function.
Chem Rev
September 2019
Division of Organic Chemistry , CSIR-National Chemical Laboratory , Dr. Homi Bhabha Road , Pune 411 008 , India.
Small cyclic peptides possess a wide range of biological properties and unique structures that make them attractive to scientists working in a range of areas from medicinal to materials chemistry. However, cyclic tetrapeptides (CTPs), which are important members of this family, are notoriously difficult to synthesize. Various synthetic methodologies have been developed that enable access to natural product CTPs and their rationally designed synthetic analogues having novel molecular structures.
View Article and Find Full Text PDFA truncated RHAMM protein for discovering novel therapeutic peptides.
Bioorg Med Chem
October 2018
Department of Chemistry, Western University, London, Ontario, Canada; Cancer Research Laboratory Program, Lawson Health Research Institute and London Regional Cancer Program, London Health Sciences Center, London, Ontario, Canada; Department of Oncology, Western University, London, Ontario, Canada; Department of Medical Imaging, Western University, London, Ontario, Canada. Electronic address:
The receptor for hyaluronan mediated motility (RHAMM, gene name HMMR) belongs to a group of proteins that bind to hyaluronan (HA), a high-molecular weight anionic polysaccharide that has pro-angiogenic and inflammatory properties when fragmented. We propose to use a chemically synthesized, truncated version of the protein (706-767), 7 kDa RHAMM, as a target receptor in the screening of novel peptide-based therapeutic agents. Chemical synthesis by Fmoc-based solid-phase peptide synthesis, and optimization using pseudoprolines, results in RHAMM protein of higher purity and yield than synthesis by recombinant protein production.
View Article and Find Full Text PDFSelenazolidine: a selenium containing proline surrogate in peptide science.
Org Biomol Chem
September 2016
Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, Université de Montpellier, CNRS, ENSCM, Place E. Bataillon, 34095 Montpellier Cedex 5, France.
In the search for new peptide ligands containing selenium in their sequences, we investigated l-4-selenazolidine-carboxylic acid (selenazolidine, Sez) as a proline analog with the chalcogen atom in the γ-position of the ring. In contrast to proteinogenic selenocysteine (Sec) and selenomethionine (SeMet), the incorporation within a peptide sequence of such a non-natural amino acid has never been studied. There is thus a great interest in increasing the possibility of selenium insertion within peptides, especially for sequences that do not possess a sulfur containing amino acid (Cys or Met), by offering other selenated residues suitable for peptide synthesis protocols.
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