Peptide drugs generally refer to short peptides of 2-50 amino acids, even longer than protein drugs. Although peptides are between small molecule drugs and biomacromolecule drugs in terms of size, ease of synthesis, selectivity, and activity, the space occupied by peptide drugs is still very limited. Peptide drugs only account for 5% of the entire drug sales, and more than half of them are insulin analogs (it is barely enough to count insulin as a peptide itself, 51 amino acids), and the rest are mainly GLP analogs and Teva's MS drug glatiramer. Therefore, peptide drugs lag far behind the other two major drugs in terms of market share and mechanism diversification.

Although peptides are more active and selective than small molecules, have no drug interactions (because they are not metabolized by the liver), have lower production costs than large molecules, are simple to develop, and have no immunogenicity, they also have fatal flaws, the most important being excessive Membrane and metabolic stability are poor. Stability can be solved by introducing unnatural amino acids, beta amino acids, side chain modifications, blocking hydrolysis sites, forming rigid macrocycles, etc., but membrane passing is an important technical obstacle. For cell surface target peptides, agonists are also the main ones. Because antagonists need to compete with endogenous ligands, the dosage is higher and injection is inconvenient. The vast majority of drug targets require inhibitors.

These technical obstacles may limit the wide application of peptide technology in modern drug discovery. Early peptide drugs mainly modified natural hormones (agonists) such as insulin and GLP-1. When natural products were popular, some natural peptide products such as vancomycin and cyclosporine were also found. There are many polypeptide toxins in snake venom. The lead of antihypertensive drug ACE inhibitor and GLP agonist exenatide are all derived from snake venom polypeptide. Now these two discovery modes are no longer mainstream, so these advantages of peptides can't be brought into play. In addition, it is not easy to transform these precursors into drugs.

Now that omics and high-throughput screening are the mainstream, peptides mainly join the mainstream new drug discovery with two entry points. The first is peptidomics, which mainly uses mass spectrometry and informatics techniques to find active peptide leads. The second is a large library of encoded peptide compounds. This second technology is the main direction of future peptide drug research. Now DNA coding combinatorial chemistry is becoming an important lead discovery technology, and coding peptide synthesis technology is actually earlier. One technique is to link the mRNA and the polypeptide encoded by the mRNA through chemical fragments. This technology can synthesize a library of hundreds of billions of peptide compounds, and then find the active lead through affinity screening, and finally rely on the combined mRNA to reverse translation into DNA and then PCR to indirectly identify the peptide sequence. The newer technology can incorporate unnatural amino acids and directly form a ring to increase the probability of discovery of high-quality leads.

There are currently 56 peptide drugs on the market, and nearly 200 peptide drugs in clinical research. With the increase of so-called nondruggable* small molecules with insufficient activity and the inability of large molecules to reach their targets, peptides may fill the gap between small molecules and biological macromolecules because of their structural diversity and complementarity with proteins (itself polypeptides). Peptide-encoding compound library can find almost any target high-activity ligand (no more than 10 amino acids), and screening technology based on binding capacity is becoming more and more mature, so peptides may enter modern new drug discovery in a brand-new attitude (not only Hormonal modification or natural product screening). Of course, the transmembrane sex is an important obstacle. To solve this problem, one is the need to further study the structure-activity relationship between chemical modification and membrane penetration, and the other is the need to invent more sensitive and accurate membrane penetration testing techniques. As long as there is enough motivation, these technical problems can be solved.