An integrated platform approach enables discovery of potent, selective and ligand-competitive cyclic peptides targeting the GIP receptor

Abstract

In any drug discovery effort, the identification of hits for further optimisation is of crucial importance. For peptide therapeutics, display technologies such as mRNA display have emerged as powerful methodologies...

Identification and engineering of potent cyclic peptides with selective or promiscuous binding through biochemical profiling and bioinformatic data analysis

“…[1][2][3] In a previous study, we demonstrated the use of an efficient, high throughput strategy from next generation sequencing (NGS) hits to identifying high affinity CP binders. 4 In this study, we aimed to investigate different avenues to develop CP binders against a protein family, with differing target binding profiles which either interact with a target selectively or provide a specific interaction profile (binding to only a subset of targets). We used mRNA-display to generate ligands for fibroblast growth factor receptors (FGF-Rs), a family of tyrosine kinases which are important targets in biomedical research, such as in cancer and metabolic disease.…”

Lessons for Oral Bioavailability: How Conformationally Flexible Cyclic Peptides Enter and Cross Lipid Membranes

“… 24 , 25 , 28 , 33 , 34 Nonetheless, designing orally bioavailable cyclic peptides with simultaneous high binding affinity to the target has been difficult so far, and is often only achieved via a tedious trial-and-error process. 35 − 38 Addressing this issue, previous studies have substantially advanced our understanding of the structure–permeability relationship of cyclic peptides, and thus provide guidance for their design as therapeutics with oral bioavailability. 25 , 30 , 39 − 46 N -Methylation of the peptide backbone, 47 − 49 changes of stereocenters, 50 , 51 tuning the amphiphilicity, 52 and side-chain modifications 53 , 54 were identified as membrane permeability factors.…”

“…Cyclic peptides are macrocycles that are composed of amino acids . In comparison to their linear counterparts, they are associated with better passive cell membrane permeability and metabolic stability. ,, Interestingly, there are examples of cyclic peptides that can be administered orally, , despite violating conventional drug-likeliness rules based on their increased molecular weight and high number of hydrogen-bonding atoms. ,,,, Nonetheless, designing orally bioavailable cyclic peptides with simultaneous high binding affinity to the target has been difficult so far, and is often only achieved via a tedious trial-and-error process. − Addressing this issue, previous studies have substantially advanced our understanding of the structure–permeability relationship of cyclic peptides, and thus provide guidance for their design as therapeutics with oral bioavailability. ,,− N -Methylation of the peptide backbone, − changes of stereocenters, , tuning the amphiphilicity, and side-chain modifications , were identified as membrane permeability factors. The effects of these modifications are unfortunately nonlinear and highly site-dependent. ,− Even small structural modifications can lead to global conformational rearrangements and thus change the physicochemical properties and membrane permeability of a compound. ,, Coherently, it has been shown that the conformational behavior of a cyclic peptide in different environments is particularly impactful for passive permeability. − …”

Lessons for Oral Bioavailability: How Conformationally Flexible Cyclic Peptides Enter and Cross Lipid Membranes

“…[24,25,28,33,34] Nonetheless, designing orally bioavailable cyclic peptides with simultaneous high binding affinity to the target has been difficult so far, and is often only achieved via a tedious trial-and-error process. [35][36][37][38] Addressing this issue, previous studies have substantially advanced our understanding of the structure-permeability relationship of cyclic peptides, and thus provide first guidance for their design as therapeutics with oral bioavailability. [25,30,[39][40][41][42][43][44][45][46] Nmethylation of the peptide backbone, [47][48][49] changes of stereocenters, [50,51] tuning the amphiphilicity, [52] and side-chain modifications [53,54] were identified as membrane permeability factors.…”