Design and study of lipopeptide inhibitors on preventing aggregation of human islet amyloid polypeptide residues 11‐20

Abstract

Type 2 diabetes mellitus, a kind of conformational disease, has become an epidemic disease, which seriously endangers the quality of life and health of human beings. The deposition of human islet amyloid polypeptide (hIAPP) has been considered as one of the major pathological features of type 2 diabetes mellitus. As lipopeptides have some hydrophobic groups, which are similar to the reported aggregation inhibitors, and some lipopeptides could prevent cells from depositing of amyloid fibrils, several potential lipopeptide inhibitors have been engineered and synthesized, which have been assessed for their inhibitory effect in preventing amyloid fibrils formation of hIAPP [11][12][13][14][15][16][17][18][19][20] by using the conventional thioflavin-T fluorescence assay and new technique microscale thermophoresis (MST). The final amyloid fibrils of hIAPP [11][12][13][14][15][16][17][18][19][20] were characterized by transmission electron microscopy. Results suggested that with the increasing length of alkyl chain, the antiaggregation efficiency of lipopeptide inhibitors towards hIAPP 11-20 increased gradually.Meanwhile, the amount of arginines, which represent the head groups of lipopeptides, may also have some influence. The binding events also showed that the inhibitory efficiency of these lipopeptide inhibitors was enhanced with the increase of affinities between lipopeptides and hIAPP [11][12][13][14][15][16][17][18][19][20] , which were obtained from MST. This study demonstrated the efficiency of lipopeptides in inhibiting the aggregation of hIAPP [11][12][13][14][15][16][17][18][19][20] and proved that MST could be regarded as an appropriate and rapid method to screen potential inhibitors of hIAPP [11][12][13][14][15][16][17][18][19][20] or other amyloid proteins. This study also broadens the types of inhibitors on inhibiting amyloid formation of hIAPP.

Targeting Human Islet Amyloid Polypeptide Aggregation and Toxicity in Type 2 Diabetes: An Overview of Peptide-Based Inhibitors

“…In a later report, the effect of macrocyclic β-sheet peptides on the relative populations of the two fibril polymorphs of hIAPP was evaluated. 82 Recently 84 The ThT assay depicted a progressive increase in the anti-aggregation ability of lipopeptide inhibitors against hIAPP (11−20) aggregation on increasing the length of alkyl chain, which indicated a significant contribution of the hydrophobicity of lipopeptides to the inhibitory effect of lipopeptides. The results revealed that increasing the number of arginine residues did not led to a higher inhibitory effect of lipopeptides.…”

“…In 2017, Mao et al engineered and synthesized several potential lipopeptide inhibitors C x -RRRR-NH 2 ( x = 4, 6, 8, 10, 12, and 14) and C14-R n -NH 2 ( n = 2, 3, 4 and 5) against hIAPP (11–20) aggregation . The ThT assay depicted a progressive increase in the anti-aggregation ability of lipopeptide inhibitors against hIAPP (11–20) aggregation on increasing the length of alkyl chain, which indicated a significant contribution of the hydrophobicity of lipopeptides to the inhibitory effect of lipopeptides.…”

Human islet amyloid polypeptide: A therapeutic target for the management of type 2 diabetes mellitus

“…However, during the second phase of clinical trials, davalintide showed no better effects than pramlintide; hence, the development of the former drug was discontinued [ 161 ]. Table S2 [ 156 , 159 , [162] , [163] , [164] , [165] , [166] , [167] , [168] , [169] , [170] , [171] , [172] , [173] , [174] , [175] , [176] , [177] , [178] , [179] , [180] , [181] , [182] , [183] , [184] , [185] , [186] , [187] , [188] , [189] , [190] , [191] , [192] , [193] , [194] , [195] , [196] , [197] , [198] ] presents some other peptide inhibitors designed and evaluated for their potential against hIAPP aggregation, for example, inhibitors derived from an internal sequence of hIAPP; those containing natural amino acids [ 162 , 169 ], d -amino acids [ 170 ], or non-natural amino acids [ 175 , 182 ]; and N -alkylated [ 186 ], cyclic [ 189 , 190 ], and conjugated [ 188 ] peptide inhibitors. In 2009, Potter et al.…”

A Lipopeptidomimetic of Transcriptional Activation Domains Selectively Disrupts the Coactivator Med25 Protein–Protein Interactions

“…N-Terminal fatty acid acylation of short peptides has been shown to increase their efficacy, stability, and cell permeability in a variety of applications. [ 8 ] Kim and coworkers, for example, reported that the palmitoylation of a heptamer discovered in a screen for proliferation PPI modulators produced inhibitors with excellent activity in vitro and in cells. [ 8d ] We hypothesized that such a strategy could produce more potent peptide inhibitors of activator–coactivator PPIs.…”