Type 2 diabetes (T2D) is a chronic metabolic disease characterized by insulin resistance and a progressive loss of pancreatic islet β-cell mass, which leads to insufficient secretion of insulin and hyperglycemia. Emerging evidence suggests that toxic oligomers and fibrils of human islet amyloid polypeptide (hIAPP) contribute to the death of β-cells and lead to T2D pathogenesis. These observations have opened new avenues for the development of islet amyloid therapies for the treatment of T2D. The peptidebased inhibitors are of great value as therapeutic agents against hIAPP aggregation in T2D owing to their biocompatibility, feasibility of synthesis and modification, high specificity, low toxicity, proteolytic stability (modified peptides), and weak immunogenicity as well as the large size of involved interfaces during self-aggregation of hIAPP. An understanding of what has been done and achieved will provide key insights into T2D pathology and assist in the discovery of more potent drug candidates for the treatment of T2D. In this article, we review various peptide-based inhibitors of hIAPP aggregation, including those derived from the hIAPP sequence and those not based on the sequence, consisting of both natural as well as unnatural amino acids and their derivatives. The present review will be beneficial in advancing the field of peptide medicine for the treatment of T2D.

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The β‐sheet breaker (BSB) peptides interfere with amyloid fibril assembly and used as therapeutic agents in the treatment of Alzheimer's disease (AD). In this regard, a simple yet effective in silico screening methodology was applied in the present study to evaluate a potential 867 pentapeptide library based on known BSB peptide, LPFFD, for destabilizing Aβ42 protofibrils. The molecular docking based virtual screening was used to filter out pentapeptides having binding affinities stronger than LPFFD. In the next step, binding free energies of the top 10 pentapeptides were evaluated using the MM‐PBSA method. The residue‐wise binding free energy analysis reveals that two pentapeptides, PVFFE, and PPFYE, bind to the surface of Aβ42 protofibril and another pentapeptide, PPFFE, bind in the core region of Aβ42 protofibril. By employing molecular dynamics simulation as a post filter for the top‐hit peptides from MM‐PBSA, the pentapeptides, PPFFE, PVFFE, and PPFYE, have been identified as potential BSB peptides for destabilizing Aβ42 protofibril structure. The conformational microstate analysis, a significant decrease in the β‐sheet content of Aβ42 protofibril, a loss in the total number of hydrogen bonds in Aβ42 protofibril, Asp23‐Lys28 salt bridge destabilization and analysis of the free energy surfaces highlight Aβ42 protofibril structure destabilization in presence of pentapeptides. Among three top‐hit pentapeptides, PPFFE displayed the most potent Aβ42 protofibril destabilization effect that shifted the energy minima toward lowest value of β‐sheet content as well as lowest number of hydrogen bonds in Aβ42 protofibril. The in silico screening workflow presented in the study highlight an alternative tool for designing novel peptides with enhanced BSB ability as potential therapeutic agents for AD.

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The molecular dynamics simulations results highlighted that the multi-target-directed ligand 6n stabilizes the native α-helix conformation of the Aβ42 monomer and induces a sizable destabilization in the Aβ42 protofibril structure.