Rationally Designed Bicyclic Peptides Prevent the Conversion of Aβ42 Assemblies Into Fibrillar Structures

Abstract

There is great interest in drug discovery programs targeted at the aggregation of the 42-residue form of the amyloid β peptide (Aβ42), since this molecular process is closely associated with Alzheimer’s disease. The use of bicyclic peptides may offer novel opportunities for the effective modification of Aβ42 aggregation and the inhibition of its cytotoxicity, as these compounds combine the molecular recognition ability of antibodies with a relatively small size of about 2 kD. Here, to pursue this approach, we rationally designed a panel of six bicyclic peptides targeting various epitopes along the sequence of Aβ42 to scan its most amyloidogenic region (residues 13–42). Our kinetic analysis and structural studies revealed that at sub-stoichiometric concentrations the designed bicyclic peptides induce a delay in the condensation of Aβ42 and the subsequent transition to a fibrillar state, while at higher concentrations they inhibit such transition. We thus suggest that designed bicyclic peptides can be employed to inhibit amyloid formation by redirecting the aggregation process toward amorphous assemblies.

Combating amyloid-induced cellular toxicity and stiffness by designer peptidomimetics

“…Natural peptide-based amyloid inhibitors offer numerous advantages over small molecule inhibitors [18][19][20][21] owing to their biological origin, biocompatibility, target-specific binding, sequence variability and ease of synthesis. [22][23][24][25][26][27][28][29] Short peptides with 16 KLVFF 20 derived from Ab42 have been shown to inhibit Ab aggregation. [30][31][32][33] The propensity of natural peptides for proteolytic cleavage and self-aggregation has led to the development of peptidomimetics-based inhibitors such as peptoids and cyclic peptides.…”

Unlocking novel therapies: cyclic peptide design for amyloidogenic targets through synergies of experiments, simulations, and machine learning

“…91 Its cyclic successor presents better in vitro potency and pharmakinetic properties 92 and could potentially alter Ab 42 aggregation. The bicyclic DesBP peptide (RAACKLGIKACTSVYHACGGKRR) was rationally designed to bind monomeric Ab 42 at residues 31-36 and 38-42 24,93 and was shown to alter the morphology of Ab 42 aggregates in a dose dependent manner. In particular, higher peptide concentrations lead to increased aggregate disorder and reduced cytotoxicity.…”

“…20 Cyclic peptides have proven to be excellent candidates for cancer therapy, 21 organ transplantation 22 and inhibition of amyloid aggregation. 23,24 Their size and functional properties ensure that the contact area is large enough to provide high selectivity, 25 their ability to form salt-bridges and hydrogen bonds can lead to strong binding affinities, 26 and cyclization increases their proteolytic stability. 27 Amyloid-forming polypeptides, such as amyloid-b (Ab 42 ), a-synuclein (a-syn) and amylin (hIAPP), share the intrinsic disorder independently of their size or residue sequence.…”

Current development of bicyclic peptides

“…In addition to the above fields, bicyclic peptides are also used in anti-AD and antitumor research. In 2021, Vendruscolo et al rationally designed a bicyclic peptide molecule based on known protein A fibrosis, which has therapeutic potential for Alzheimer's disease [100]. In 2021, Zhou et al designed stapled α-helical peptides with a bicyclic structure.…”