No matter it is the emerging peptide polypeptide new economy industry or the classic peptide polypeptide industry, they are facing the problem of difficult discovery and modification of peptide drugs. Mastering peptide polypeptide discovery and modification technology is of vital importance to enterprise competitiveness.
As one of the most profressional peptide api manufacturers, we would like to share with you present peptide drug discovery strategies.
Endogenous peptide hormones: Research on endogenous peptide hormones mainly focuses on human signaling hormones. Due to their very short half-life of only a few minutes, their clinical application is hindered. Scientists use various medicinal chemistry methods to modify peptide polypeptide hormones to improve their stability and to improve other properties. Two representative examples are somatostatin and insulin, which have been successfully marketed by improving the stability, efficacy and selectivity of these endogenous ligands through chemical modification such as site-specific mutations, N-terminal or C-terminal extensions, peptide loop formation, and conjugation with long-chain hydrocarbons.
Natural active peptides: How to screen out peptide polypeptides with specific biological activities from complex natural biological systems is a key technology for the creation and application of natural active peptide polypeptides [Chinese Journal of Biotechnology. 2021, 37(6): 2166-2180]. The most direct method of screening active peptide polypeptides is to use physical methods to extract them from natural biological resources and their enzymatic or fermentation products, and then further explore their physiological activities, or to screen and isolate biologically active peptide polypeptides with specific functions from natural resources. Cyclosporin is a neutral, hydrophobic cyclic peptide containing 11 residues isolated from fungi. Modification of known peptide polypeptides with known sequences and functions can result in newer and more effective active peptide polypeptides.
Venom proteomics and display technology: "Venom proteomics" and various "display technologies" are two key technologies for discovering therapeutic lead peptide polypeptides. Venom proteomics uses bioinformatics to analyze the genome and transcriptome data of poisonous animals, as well as proteomics data obtained from crude venom samples, to identify a large number of venom peptide sequences, which are then synthesized or recombinantly generated and used for screening therapeutic targets. Display technologies can generate large peptide libraries targeting therapeutic targets, including phage display technology and mRNA display technology. This process usually produces high-affinity target binding molecules after several rounds of screening, and then uses medicinal chemistry strategies to improve the drug properties of these leads. For example, glutathione is a pentapeptide that can help protect the body from disease, and improve insulin sensitivity, among other benefits.
If you are interested in it, we can have a detailed list of peptide drugs.
The purposes of active peptide modification are diverse and mainly include improving the affinity and selectivity of active peptides with receptors; enhancing the pharmacokinetic stability of peptide polypeptide molecules, reducing their degradation or elimination in vivo; improving the membrane permeability of active peptides; improving the water solubility of hydrophobic peptides, etc. Depending on the purpose of modification and whether the peptide chain skeleton is modified, these modification strategies can be divided into two categories: one is the modification of the peptide chain skeleton, including non-natural amino acid modification, pseudo-peptide strategy, retro-inversion strategy, cyclization strategy, N-terminal or C-terminal structural modification, α-helix solidification, and conjugation peptides. The other is to introduce other groups into the peptide skeleton to optimize the structure and improve the performance on the basis of unchanged peptide polypeptide skeleton, including advanced fatty acid modification, polyethylene glycol modification, protein fusion strategy (including Fc-fusion protein/Peptibody), cholesterol modification, use of disulfide bond mimetics, etc. By comprehensively using these structural modification strategies for lead compounds, it is possible to significantly improve the drug-likeness of peptide compounds and provide theoretical guidance and practical experience for developing innovative peptide drugs.