RESUMO
Protein misfolding into amyloid fibrils is linked to more than 40 as yet incurable cell- and neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and typeâ 2 diabetes. So far, however, only one of the numerous anti-amyloid molecules has reached patients. This Minireview gives an overview of molecular strategies and peptide chemistry "tools" to design, develop, and discover peptide-based molecules as anti-amyloid drug candidates. We focus on two major inhibitor rational design strategies: 1)â the oldest and most common strategy, based on molecular recognition elements of amyloid self-assembly, and 2)â a more recent approach, based on cross-amyloid interactions. We discuss why peptide-based amyloid inhibitors, in particular their advanced generations, can be promising leads or candidates for anti-amyloid drugs as well as valuable tools for deciphering amyloid-mediated cell damage and its link to disease pathogenesis.
Assuntos
Amiloide/antagonistas & inibidores , Peptídeos/química , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Amiloide/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Desenho de Fármacos , Humanos , Peptídeos/metabolismo , Peptídeos/farmacologia , Agregados Proteicos/efeitos dos fármacos , Dobramento de ProteínaRESUMO
Amyloid self-assembly of islet amyloid polypeptide (IAPP) is linked to pancreatic inflammation, ß-cell degeneration, and the pathogenesis of type 2 diabetes (T2D). The multifunctional host-defence peptides (HDPs) cathelicidins play crucial roles in inflammation. Here, we show that the antimicrobial and immunomodulatory polypeptide human cathelicidin LL-37 binds IAPP with nanomolar affinity and effectively suppresses its amyloid self-assembly and related pancreatic ß-cell damage inâ vitro. In addition, we identify key LL-37 segments that mediate its interaction with IAPP. Our results suggest a possible protective role for LL-37 in T2D pathogenesis and offer a molecular basis for the design of LL-37-derived peptides that combine antimicrobial, immunomodulatory, and T2D-related anti-amyloid functions as promising candidates for multifunctional drugs.