Peptides were synthesized and purified to >95% purity at Eli Lilly and Company or purchased from CPC Scientific or Tocris. GLP-1(9-36)NH2, GLP-1(7-36)NH2, OXM(1-37)OH and GIP(1-42)NH2 were used for pharmacology experiments, and GLP-1(7-37)OH was used for cryo-EM studies.
Abstract
Drugs that promote the association of protein complexes are an emerging therapeutic strategy. We report discovery of a G protein-coupled receptor (GPCR) ligand that stabilizes an active state conformation by cooperatively binding both the receptor and orthosteric ligand, thereby acting as a ‘molecular glue’. LSN3160440 is a positive allosteric modulator of the GLP-1R optimized to increase the affinity and efficacy of GLP-1(9-36), a proteolytic product of GLP-1(7-36). The compound enhances insulin secretion in a glucose-, ligand- and GLP-1R-dependent manner. Cryo-electron microscopy determined the structure of the GLP-1R bound to LSN3160440 in complex with GLP-1 and heterotrimeric Gs. The modulator binds high in the helical bundle at an interface between TM1 and TM2, allowing access to the peptide ligand. Pharmacological characterization showed strong probe dependence of LSN3160440 for GLP-1(9-36) versus oxyntomodulin that is driven by a single residue. Our findings expand protein–protein modulation drug discovery to uncompetitive, active state stabilizers for peptide hormone receptors.
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Genomics research shows that more than a million proteins are encoded by approximately 30,000 human genes. Proteomics, the study of proteins encoded by the genome, includes identifying post-translational modifications, structural analyses, protein localization studies, and protein quantitation. Mass spectroscopybased techniques have evolved as a powerful tool in proteomics. Stable isotope-labeled peptides (SIL peptides) are chemically and physically indistinguishable from their endogenous counterparts concerning retention time, ionization efficiency, and fragmentation pathways.
Peptides play a vital role in the pharmaceutical industry and drug therapeutic development; however, their in vivo applications are sometimes limited due to fast degradation by proteases, poor solubility, antigenic responses, and glomerular filtration in the kidney. The covalent attachment of polyethylene glycol (PEG) chains to peptides is one approach that can reduce immunogenicity, improve solubility, and reduce renal clearance.
Hydrocarbon-stapled peptides are locked into their bioactive alpha-helical conformation through the site-specific introduction of a chemical brace, an all-hydrocarbon staple. The idea of peptide stapling was introduced to overcome the limitations of two broad classes of therapeutic agents (small molecules and protein biologics) in targeting intracellular protein-protein interactions. Small molecules only work on proteins with a specific surface feature, and most protein biologics do not penetrate cells. Because stapled peptides are locked into a stabilized α-helical structure (the most common element of protein secondary structures), they can easily penetrate cells.
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Mogford, Jon E., George E. Davis, Steven H. Platts, and Gerald A. Meininger. Circulation research 79, no. 4 (1996): 821-826.
Locmi-AKH-I, cycloAKH (cyclo[LNFTPNWG]
CPC Scientific is pleased to announce and welcome David A. Godkin as VP of Business Operations! David will be responsible for the growth and development of our HR department and facilities management division. He brings 20+ years of experience in human resources and facility operations from the peptide industry. We are confident David will have […]
Bekdemir, Ahmet, Eden EL Tanner, Jesse Kirkpatrick, Ava P. Soleimany, Samir Mitragotri, and Sangeeta N. Bhatia Advanced Healthcare Materials (2022): 2102685.
Peptides [TDN-qFAM, C-(PEG)2-K(CPQ2)-GGGSRPfGG-5FAM] were obtained from Tufts University Peptide Core Facility or CPC Scientific, Inc (USA)
Mac, Quoc D., Anirudh Sivakumar, Hathaichanok Phuengkham, Congmin Xu, James R. Bowen, Fang-Yi Su, Samuel Z. Stentz et al. Nature Biomedical Engineering (2022): 1-15.
"FITC-labelled GzmB substrate peptides with internal quencher ((5FAM)aIEFDSG(K-CPQ2)kkc) were synthesized by CPC Scientific and used for all in vitro activity assays. [..] Quenched fluorescent peptides for screening candidate substrates ((5FAM)-{substrate}-(K-DABCYL)-amide"
Lopez, Andrea, Denis E. Reyna, Nadege Gitego, Felix Kopp, Hua Zhou, Miguel A. Miranda-Roman, Lars Ulrik Nordstrøm et al. Nature Communications 13, no. 1 (2022): 1-18.
"Hydrocarbon-stapled peptide corresponding to the BH3 domain of BIM, FITC-BIM SAHBA2: FITC-βAla-EIWIAQELRS5IGDS5F’NAYYA-CONH2, where S5 represents the non-natural amino acid inserted for olefin metathesis, was synthesized, purified at >95% purity by CPC Scientific Inc."
Lenz, Morgan R., Shih-Yen Tsai, Anne E. Roessler, Yang Wang, Periannan Sethupathi, W. Keith Jones, Gwendolyn L. Kartje, and William H. Simmons. Journal of Pharmacology and Experimental Therapeutics 380, no. 3 (2022): 220-229.
"The ST-115 [ [(S)-2-mercapto-4-methylpentanoyl]-4(S)-fluoro-Pro-Pro-3(R)-beta-Pro] preparation used in this study was custom synthesized by CPC Scientific, Inc., (Sunnyvale, CA), a GMP-capable company. The synthetic scheme is detailed in US patent"