The concept of developing novel anti-amyloid inhibitors in the scientific community has engrossed remarkable research interests and embraced significant potential to resolve numerous pathological conditions including neurological as well as non-neuropathic disorders associated with amyloid protein aggregation. These pathological conditions have harmful effects on cellular activities which include malfunctioning of organs and tissue, cellular impairment, etc. To date, different types of small molecular probes like polyphenolic compounds, nanomaterials, surfactants, etc. have been developed to address these issues. Recently synthetic polymeric materials are extensively investigated to explore their role in the protein aggregation pathway. On the basis of these perspectives, in this review article, we have comprehensively summarized the current perspectives on protein misfolding and aggregation and importance of therapeutic approaches in designing novel effective inhibitors. The main purpose of this review article is to provide a detailed perspective of the current landscape as well as trailblazing voyage of various inhibitors ranging from small molecular probes to polymeric scaffolds in the field of protein misfolding and aggregation. A particular emphasis is given on the structural role and molecular mechanistic pathway involved in modulating the aggregation pathway to further inspire the researchers and shed light in this bright research field.
Insulin fibril formation is considered as the hallmark of several debilitating pathological conditions. To develop effective therapeutics that are able to control the amyloidogenesis process and inhibit fibril formation, herein we have designed a side-chain proline (Pro)-based homopolymer and block copolymers through the reversible addition−fragmentation chain transfer (RAFT) polymerization technique and further explored their obligatory role in the in vitro insulin fibrillation process. Using a variety of biophysical tools, including turbidity measurements, thioflavin T (ThT) fluorescence kinetics, tyrosine (Tyr) fluorescence study, Nile red (NR) fluorescence assay, dynamic light scattering (DLS) study, circular dichroism (CD) measurements, and isothermal titration calorimetry (ITC) techniques, we demonstrated that Pro-based polymers can significantly inhibit the insulin fibrillation process. Among them, the Pro-based homopolymer acts as the most potent inhibitor of insulin fibrillation as confirmed by ThT assay, CD study, and transmission electron microscopic (TEM) analysis. Tyrosine fluorescence measurements and NR fluorescence assay revealed that hydrophobic interactions are the crucial factor that mainly controls the inhibition process. Apart from hydrophobic interactions, polar interactions may also be responsible for the inhibition process as evaluated by ITC study.
The emission spectrum of a fluorophore undergoing excited state proton transfer (ESPT) often exhibits two distinct bands each representing emissions from protonated and deprotonated forms. The relative contribution of the two bands, best represented by an emission intensity ratio ( R) (intensity maximum of the protonated band/intensity maximum of the deprotonated band), is an important parameter which usually denotes feasibility or promptness of the ESPT process. However, the use of a ratio is only limited to the interpretation of steady-state fluorescence spectra. Here, for the first time, we exploit the time dependence of the ratio ( R( t)), calculated from time-resolved emission spectra (TRES) at different times, to analyze ESPT dynamics. TRES at different times were fitted with a sum of two log-normal functions representing each peak, and then, the peak intensity ratio, R( t), was calculated and further fitted with an analytical function. Recently, a time-resolved area-normalized emission spectra (TRANES)-based analysis was presented where the decay of protonated emission or the rise of deprotonated emission intensity conveniently accounts for the ESPT dynamics. We show that these two methods are equivalent but the new method provides more insights on the nature of the ESPT process.
To develop anti-amyloidogenic inhibitors for ameliorating the treatment of diabetes, herein, we have synthesized amphiphilic block copolymers with side-chain fatty acid (FA) moieties via reversible addition fragmentation chain-transfer (RAFT) polymerization....
To understand the effect of cholic acid (CA)-based charge variable polymeric architectures on modulating the insulin aggregation process, herein, we have designed side-chain cholate-containing charge variable polymers. Three different types of copolymers from 2-(methacryloyloxy)ethyl cholate with anionic or cationic or neutral units have been synthesized by reversible addition-fragmentation chain transfer polymerization. The effects of these copolymers on the insulin fibrillation process was studied by multiple biophysical approaches including different types of spectroscopic and microscopic analyses. Interestingly, the CA-based cationic polymer (CP-10) was observed to inhibit the insulin fibrillation process in a dose-dependent manner and to act as an effective anti-amyloidogenic agent. Corresponding anionic (AP-10) and neutral (NP-10) copolymers with cholate pendants remained insignificant in controlling the aggregation process. Tyrosine fluorescence assays and Nile red fluorescence measurements demonstrate the role of hydrophobic interaction to explain the inhibitory potencies of CP-10. Furthermore, circular dichroism spectroscopic measurements were carried out to explore the secondary structural changes of insulin fibrils in the presence of cationic polymers with and without cholate moieties. Isothermal titration calorimetry measurements revealed the involvement of electrostatic polar interaction between the CA-based cationic polymer and insulin at different stages of fibrillation. Overall, this work demonstrates the efficacy of the CA-based cationic polymer in controlling the insulin aggregation process and provides a novel dimension to the studies on protein aggregation.
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