Research progress of polypeptide drugs

A review on the research progress of polypeptide drugs was published in the Journal of pharmaceutical chemistry, which comprehensively discussed the current research and development status and cutting-edge technology of polypeptide drugs Peptide drugs generally refer to short peptides of 2-50 amino acids, and even protein drugs are longer Although the properties of polypeptides, such as size, synthesis difficulty, selectivity and activity, are between small molecule drugs and biomacromolecule drugs, the space occupied by polypeptides is very limited Polypeptide drugs account for only 5% of the total drug sales, most of which are insulin analogues, and the rest are mainly GLP analogues and MS drugs of TIWA, gratire So peptide drugs are far behind the other two major drugs in market share and mechanism diversification Although polypeptides have better activity and selectivity than small molecules, no drug interaction (because they are not metabolized by liver), lower production cost than large molecules, simple research and development, and no immunogenicity, they also have fatal defects, mainly poor transmembrane and metabolic stability Stability can be solved by introducing non natural amino acids, beta amino acids, side chain modification, blocking hydrolysis sites, forming rigid macrocycles and other technologies, but transmembrane is an important technical obstacle Because antagonists need to compete with endogenous ligands, so the dosage should be higher and injection is not convenient Most of the target of the drug is to need inhibitors These technical barriers may limit the wide application of peptide technology in modern drug discovery Early peptide drugs mainly modified natural hormones (agonists), such as insulin, GLP-1, etc., and some natural peptide products, such as vancomycin and cyclosporine, were also found when natural products were prevalent There are many polypeptide toxins in snake venom ACE inhibitors and exenatide, GLP agonist, are all derived from snake venom polypeptides Now these two discovery patterns are no longer mainstream, so these advantages of polypeptides can not play out In addition, it is not easy to transform these precursors into drugs, which used to be a very popular research direction, but the progress is slow, and now there are not many people who have done it At present, with the mainstream of histology and high-throughput screening, peptides are mainly added to the mainstream of new drug discovery at two entry points One is polypeptide group, which mainly uses mass spectrometry and information technology to find the active polypeptide precursor The second is the super coding peptide library This second technology is the main direction of peptide drug research in the future Now DNA coding combinatorial chemistry is becoming an important precursor discovery technology, while the synthesis technology of coding polypeptide is actually earlier One technique is to link the mRNA with the peptide encoded by the mRNA through a chemical fragment This technology can synthesize hundreds of billions of peptide libraries, then find the active precursor through affinity screening, and finally translate the linked mRNA into DNA and then identify the peptide sequence indirectly by PCR The updated technology can be incorporated into non natural amino acids and directly modified into rings to increase the probability of finding high-quality precursors Now there are 56 polypeptide drugs on the market, and nearly 200 polypeptide drugs that have entered the clinical research With the increase of the so-called nondraggable * small molecule's insufficient activity and large molecule's inability to reach the target, peptide may fill the gap between small molecule and biological macromolecule because of its structural diversity and complementary with protein (itself is peptide) The peptide library can find almost any target high active ligand (no more than 10 amino acids), and the screening technology based on binding power is becoming more and more mature, so the peptide may enter the modern new drug discovery with a new attitude (not only hormone transformation or natural product screening) Of course, transmembrane is an important obstacle To solve this problem, first, we need to further study the structure-activity relationship between chemical modification and transmembrane, second, we need to invent more sensitive and accurate testing technology of transmembrane As long as there is enough power, these technical problems can be solved.