Monomer-targeting affinity peptide inhibitors of amyloid with no self-fibrillation and low cytotoxicity

Abstract

A monomer-targeting strategy based on solution-phase biopanning to obtain peptide inhibitors increases the suppression efficiency and reduces the cytotoxicity of amylin.

Deciphering the Inhibitory Mechanism of hIAPP‐Derived Fragment Peptide Against hIAPP Aggregation in Type 2 Diabetes**

“…The absence of β‐sheet structures in the conformational ensemble of the hIAPP‐ANFLVH complex is consistent with circular dichroism (CD) results, which highlighted the prevention of the formation of β‐sheet in hIAPP on the addition of ANFLVH peptide at equimolar or higher concentrations [39] . The results of the secondary structure analysis are consistent with Xuan et al., which reported that LA12 (LTPHKHHKHLHA) stabilized hIAPP in a random coil conformation, which, in turn, prevented the conformational transition to aggregation‐prone β‐sheet conformation and formation of hIAPP fibrils [38] . Further, Lao et al.…”

“…[39] The results of the secondary structure analysis are consistent with Xuan et al, which reported that LA12 (LTPHKHHKHLHA) stabilized hIAPP in a random coil conformation, which, in turn, prevented the conformational transition to aggregation-prone β-sheet conformation and formation of hIAPP fibrils. [38] Further, Lao et al also highlighted the prevention of the formation of βsheet conformation by hIAPP dimer in the presence of dopamine by employing replica-exchange MD simulations. [53] Dopamine displayed preferential binding with Arg11, Leu12, Phe15, His18, Phe23, Ile26, Leu27, and Tyr37 residues of hIAPP and prevented the β-sheets formation in the amyloidogenic regions of hIAPP.…”

“…[32][33][34] In addition to peptides derived from the amyloidogenic fragments of hIAPP, several other peptide-based inhibitors have been tested against hIAPP aggregation and hIAPP-induced cytotoxicity. [35][36][37][38] Potter et al synthesized numerous peptides derived from the sequence of IAPP and identified hexapeptide ANFLVH as a potent inhibitor of IAPP aggregation. [39] ANFLVH inhibited IAPP aggregation in vitro and in human islet cultures, which significantly enhanced the islet cell viability.…”

“…A large number of peptides derived from the amyloidogenic fragments of hIAPP or by slight structural changes in these fragments have been evaluated as inhibitors of hIAPP aggregation and hIAPP‐induced cytotoxicity [32–34] . In addition to peptides derived from the amyloidogenic fragments of hIAPP, several other peptide‐based inhibitors have been tested against hIAPP aggregation and hIAPP‐induced cytotoxicity [35–38] . Potter et al.…”

Conformation-reconstructed multivalent antibody mimic for amplified mitigation of human islet amyloid polypeptide amyloidogenesis

“…9,[11][12][13] Until now, a stream of strategies have been applied to prevent and suppress the IAPP self-assembly process. [14][15][16][17][18][19][20][21] However, most amyloidogenesis inhibitors developed based on these endeavors are effective only at molar excess, mainly because of the lack of high binding affinity or specificity.…”