ArticleBiopolymers2008
Structure-activity relationship and metabolic stability studies of backbone cyclization and N-methylation of melanocortin peptides.
Article in Biopolymers, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers, 1 of them a synthesis that pooled it.
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Who cites it
19 citing papers in PubMed, 1 synthesis or guideline pooled it.
- The melanocortin-4 receptor as target for obesity treatment: a systematic review of emerging pharmacological therapeutic options.International journal of obesity (2005) · 2014Pooled it
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- Peptides and Peptidomimetics as Potential Antiobesity Agents: Overview of Current Status.Frontiers in nutrition · 2019Review
- A Novel Substance P-Based Hydrogel for Increased Wound Healing Efficiency.Molecules (Basel, Switzerland) · 2018Article
- Conversion of Protein Active Regions into Peptidomimetic Therapeutic Leads Using Backbone Cyclization and Cycloscan - How to Do it Yourself!Current topics in medicinal chemistry · 2018Review
- Novel approaches to the design of bioavailable melanotropins.Expert opinion on drug discovery · 2017Review
- Motif mediated protein-protein interactions as drug targets.Cell communication and signaling : CCS · 2016Review
- Strategic approaches to optimizing peptide ADME properties.The AAPS journal · 2015Review
- Automated solid-phase peptide synthesis to obtain therapeutic peptides.Beilstein journal of organic chemistry · 2014Review
- New analogs of the clinical complement inhibitor compstatin with subnanomolar affinity and enhanced pharmacokinetic properties.Immunobiology · 2013Article
- Getting in shape: controlling peptide bioactivity and bioavailability using conformational constraints.ACS chemical biology · 2013Review
- Cyclisation increases the stability of the sea anemone peptide APETx2 but decreases its activity at acid-sensing ion channel 3.Marine drugs · 2012Article
- Parallel synthesis of peptide-like macrocycles containing imidazole-4,5-dicarboxylic acid.Molecules (Basel, Switzerland) · 2012Article
- Application of ring-closing metathesis macrocyclization to the development of Tsg101-binding antagonists.Bioorganic & medicinal chemistry letters · 2010Article
Corrections and comments
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9 authors.
Funding
Abstract
Backbone cyclization (BC) and N-methylation have been shown to enhance the activity and/or selectivity of biologically active peptides and improve metabolic stability and intestinal permeability. In this study, we describe the synthesis, structure-activity relationship (SAR) and intestinal metabolic stability of a backbone cyclic peptide library, BL3020, based on the linear alpha-Melanocyte stimulating hormone analog Phe-D-Phe-Arg-Trp-Gly. The drug lead, BL3020-1, selected from the BL3020 library (compound 1) has been shown to inhibit weight gain in mice following oral administration. Another member of the BL3020 library, BL3020-17, showed improved biological activity towards the mMC4R, in comparison to BL3020-1, although neither were selective for MC4R or MC5R. N-methylation, which restrains conformational freedom while increasing metabolic stability beyond that which is imparted by BC, was used to find analogs with increased selectivity. N-methylated backbone cyclic libraries were synthesized based on the BL3020 library. SAR studies showed that all the N-methylated backbone cyclic peptides demonstrated reduced biological activity and selectivity for all the analyzed receptors. N-methylation of active backbone cyclic peptides destabilized the active conformation or stabilized an inactive conformation, rendering the peptides biologically inactive. N-methylation of backbone cyclic peptides maintained stability to degradation by intestinal enzymes.
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