Non-covalent S⋯O interactions control conformation in a scaffold that disrupts islet amyloid polypeptide fibrillation

Abstract

Rationally-designed peptidomimetics that selectively recognise protein surfaces have the potential to mediate protein-misfolding conditions.

β‐Strand Mimicry: Exploring Oligothienylpyridine Foldamers

“…These results are consistent with previously published theoretical calculations in which an electron‐deficient divalent S atom has two areas of positive electrostatic potential, a consequence of the low‐lying σ* orbitals of the C–S bond that are available for interaction with an electron donor such as nitrogen . Consequently, the intermolecular N ··· S interaction was pointed out as a conformational stabilizing element introducing an “N,S‐ cis ‐locked” coplanar arrangement in biaryl systems in a manner analogous to that of noncovalent S ··· O interactions, which has been used as a conformational control element in the α‐helical mimetic benzothiazol‐thiophene scaffold synthesized by Hamilton's group . Moreover, we also observed that the coplanar arrangement in the biaryl can be achieved when the N atom lies in the direct neighborhood of the junction and the other three atoms are H ar (group A3).…”

A thiocyanopalladation/carbocyclization transformation identified through enzymatic screening: stereocontrolled tandem C–SCN and C–C bond formation

“…Beyond their utility as an IR- or Raman-probes, 40 in medicinal chemistry circles, thiocyanates have served as synthetic intermediates to useful drug-like heterocyclic scaffolds, particularly fused cyclic thioureas 62 and substituted benzothiazoles 61a , 63 such as the 2-amino-benzothiazole-based peptidomimetic oligomers recently described by Hamilton that disrupt amyloid peptide fibrillation. 64 In this study, we have highlighted the chemical versatility of the thiocyanate moiety, by generating an array of structural variants from a common NP core structure ( Scheme 4 ), 29 , 30 an approach that clearly holds promise for DOS applications. 45 , 46 , 65 In surveying the literature, it seems clear that the thiocyanate moiety is an under-utilized functionality for chemical diversification in library development.…”

Crystal Structure of the DFNKF Segment of Human Calcitonin Unveils Aromatic Interactions between Phenylalanines

“…Elucidating the structure and formation mechanism of amyloid fibrils is of paramount importance for current structural biology . However, the limited order of fibrils isolated from diseased tissues, as well as their great morphological diversity, have limited their atomic‐level structural determination.…”