RESUMO
Abberent protein-protein interactions potentiate many diseases and one example is the toxic, self-assembly of α-Synuclein in the dopaminergic neurons of patients with Parkinson's disease; therefore, a potential therapeutic strategy is the small molecule modulation of α-Synuclein aggregation. In this work, we develop an Oligopyridylamide based 2-dimensional Fragment-Assisted Structure-based Technique to identify antagonists of α-Synuclein aggregation. The technique utilizes a fragment-based screening of an extensive array of non-proteinogenic side chains in Oligopyridylamides, leading to the identification of NS132 as an antagonist of the multiple facets of α-Synuclein aggregation. We further identify a more cell permeable analog (NS163) without sacrificing activity. Oligopyridylamides rescue α-Synuclein aggregation mediated Parkinson's disease phenotypes in dopaminergic neurons in early and post disease Caenorhabditis elegans models. We forsee tremendous potential in our technique to identify lead therapeutics for Parkinson's disease and other diseases as it is expandable to other oligoamide scaffolds and a larger array of side chains.
Assuntos
Caenorhabditis elegans , Neurônios Dopaminérgicos , Doença de Parkinson , alfa-Sinucleína , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genética , Caenorhabditis elegans/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/patologia , Animais , Humanos , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Fenótipo , Agregados Proteicos/efeitos dos fármacos , Modelos Animais de Doenças , Agregação Patológica de Proteínas/metabolismo , Agregação Patológica de Proteínas/tratamento farmacológico , Piridinas/farmacologia , Piridinas/química , Amidas/farmacologia , Amidas/químicaRESUMO
Two-photon polymerization (TPP) microfabrication technology can freely prepare micro/nano structures with different morphologies and high accuracy for micro/nanophotonics, micro-electromechanical systems, microfluidics, tissue engineering and drug delivery. With the broad application of 3D microstructures in the biomedical field, people have paid more attention to the physicochemical properties of the corresponding materials such as biocompatibility, biodegradability, stimuli responsiveness and immunogenicity. Therefore, microstructures composed of biocompatible synthetic polymers, polysaccharides, proteins and their complexes have been widely studied. In this review, we briefly summarize the TPP mechanism, the photoinitiators for TPP microfabrication, photoresist based on biomaterials, their corresponding microstructures and subsequently their biomedical applications. We will point out the issues in previous research and provide a useful perspective on the future development of TPP microfabrication technology.
