Unconventional insulins from predators and pathogens

From Natural Insulin to Designed Analogs: A Chemical Biology Exploration

“… [13] Structural determination of the complex between the insulin receptor and Vh‐Ins‐HALQ revealed that the A23Leu from the extended A chain occupies the same 3D space as B24Phe from human insulin, crucial for receptor binding. These examples emphasize the evolutionary strength of the venom insulin molecules to develop unique strategies for insulin receptor binding [15] . Owing to the absence of the C‐terminal B chain, these bioactive truncated insulins are monomeric and potentially useful for ultrafast‐acting properties in subcutaneous insulin administration [13] …”

“…These examples emphasize the evolutionary strength of the venom insulin molecules to develop unique strategies for insulin receptor binding. [15] Owing to the absence of the C-terminal B chain, these bioactive truncated insulins are monomeric and potentially useful for ultrafast-acting properties in subcutaneous insulin administration. [13] Viral insulin-like peptides (VILPs) provide another example of naturally occurring unconventional insulin.…”

Disulfide-Directed Multicyclic Peptide Libraries for the Discovery of Peptide Ligands and Drugs

“…Unlike linear peptides that are flexible in structure, multicyclic peptides usually have stable 3D structures with improved physicochemical characteristics for therapeutic effect. − Lying between large biologics and small chemicals in size, multicyclic peptides possess the potential of integrating the best attributes of both, representing an intriguing modality for drug discovery and development. − Currently, multicyclic peptides with biological functions mainly come from naturally occurring peptides constrained by disulfide or thioether bridges and de novo designed or selected peptides with the incorporation of disulfide or other crosslinkers. − Among them, disulfide-rich peptides (DRPs) including conotoxins, cyclotides, cystine knots, and those designed de novo are most extensively explored as potent biologically active compounds. − , These peptides can take advantage of their intrinsic folding property to direct the disulfide pairing and formation of stable protein-like 3D structures competent for target recognition. − Despite this, the structural variety of DRPs is limited to several privileged natural and designer scaffolds, significantly hindering the development of multicyclic peptide ligands and therapeutics. To address this issue, recently, we have developed a new class of methods relying on the use of disulfide-directing motifs to design and select DRPs with new structures and functions from random sequences. − Compared to traditional DRPs, these DRPs bearing disulfide-directing motifs can fold more precisely with regard to disulfide pairing and are tolerant to more extensive sequence manipulations.…”

Serine-mediated hydrazone ligation displaying insulin-like peptides on M13 phage pIII

“…20 Insulin is a life-saving treatment for Type 1 diabetes (T1D), and many people with Type 2 diabetes (T2D) and gestational diabetes (GDM) to achieve normoglycemia. 21,22 Structurally, insulin comprises two polypeptide chains, the A chain (consisting of 21 amino acids) and the B chain (composed of 30 amino acids), which are linked by two interchain disulfide bonds, along with a third intramolecular disulfide bond within the A chain. 23 The insulin B chain C-terminal region (B23-B30) is of particular significance in insulin receptor (IR) binding, 24,25 regulating insulin activity, 26,27 and influencing protein aggregation.…”