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Biophysical Insights into Implications of PEG-400 on the ?-Crystallin Structure: Multispectroscopic and Microscopic Approach.

ABSTRACT: Aggregation and precipitation of ?-crystallin play a vital role in the cataract development. This study was targeted to delineate the effect of PEG-400 on the structural integrity of ?-crystallin employing a multispectroscopic and microscopic approach. Intrinsic fluorescence and UV-vis spectroscopy suggested alterations in the tertiary structure of ?-crystallin, namely global transition of native ?-crystallin to a non-native form in the presence of PEG-400. Circular dichroism spectroscopy suggested secondary structural transition in a native conformation of ?-crystallin in the presence of PEG-400. Loss in the native conformation of ?-crystallin is implicated in cataract developments, thus highlighting the clinical significance of this work. Further, a significant increase in ANS fluorescence of PEG-400-incubated ?-crystallin (7 days) suggested this non-native form to be molten globule (MG)-like state. Increased Thioflavin T fluorescence (ThT) and congo red (CR) absorbance along with transmission electron microscopy (TEM) confirmed the formation of the aggregates of ?-crystallin after prolonged incubation with PEG-400. Insights into PEG-400-induced structural alterations can provide a platform to search for new therapeutic molecules that can combat ?-crystallin-directed eye diseases.

SUBMITTER: Shamsi A

PROVIDER: S-EPMC7409245 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Biophysical Insights into Implications of PEG-400 on the α-Crystallin Structure: Multispectroscopic and Microscopic Approach.

Shamsi Anas A Mohammad Taj T Anwar Saleha S Hassan Md Imtaiyaz MI Ahmad Faizan F Hasan Ikramul I Islam Asimul A

ACS omega 20200721 30

Aggregation and precipitation of α-crystallin play a vital role in the cataract development. This study was targeted to delineate the effect of PEG-400 on the structural integrity of α-crystallin employing a multispectroscopic and microscopic approach. Intrinsic fluorescence and UV-vis spectroscopy suggested alterations in the tertiary structure of α-crystallin, namely global transition of native α-crystallin to a non-native form in the presence of PEG-400. Circular dichroism spectroscopy sugges ...[more]

PMID: 32775924

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Project description:Background & aimsThe pharmacokinetics and pharmacodynamics of pegylated-interferon-alpha-2a (PEG-IFN) have not been described in HCV/HIV co-infected patients. We sought to estimate the pharmacokinetics and pharmacodynamics of PEG-IFN and determine whether these parameters predict treatment outcome.MethodsTwenty-six HCV/human immunodeficiency virus (HIV)-co-infected patients were treated with a 48-week regimen of PEG-IFN (180 microg/week) plus ribavirin (11 mg/kg/day). HCV RNA and PEG-IFN concentrations were obtained from samples collected until week 12. A modeling framework that includes pharmacokinetic and pharmacodynamic parameters was developed.ResultsFive patients discontinued treatment. Seven patients achieved a sustained virological response (SVR). PEG-IFN concentrations at day 8 were similar to steady-state levels (p=0.15) and overall pharmacokinetic parameters were similar in SVRs and non-SVRs. The maximum PEG-IFN effectiveness during the first PEG-IFN dose and the HCV-infected cell loss rate (delta), were significantly higher in SVRs compared to non-SVRs (median 95% vs. 86% [p=0.013], 0.27 vs. 0.11 day(-1) [p=0.006], respectively). Patients infected with HCV genotype 1 had a significantly lower average first-week PEG-IFN effectiveness (median 70% vs. 88% [p=0.043]), however, 4- to 12-week PEG-IFN effectiveness was not significantly different compared to those with genotype 3 (p=0.114). Genotype 1 had a significantly lower delta compared to genotype 3 (median 0.14 vs. 0.23 day(-1) [p=0.021]). The PEG-IFN concentration that decreased HCV production by 50% (EC(50)) was lower in genotype 3 compared to genotype 1 (median 1.3 vs. 3.4 [p=0.034]).ConclusionsBoth the HCV-infected cell loss rate (delta) and the maximum effectiveness of the first dose of PEG-IFN-alpha-2a characterised HIV co-infected patients and were highly predictive of SVR. Further studies are needed to validate these viral kinetic parameters as early on-treatment prognosticators of response in patients with HCV and HIV.

Project description:The demonstration of chaperone-like activity in peptides (mini-chaperones) derived from ?-crystallin's chaperone region has generated significant interest in exploring the therapeutic potential of peptide chaperones in diseases of protein aggregation. Recent studies in experimental animals show that mini-chaperones could reach intended targets and alter the disease phenotype. Although mini-chaperones show potential benefits against protein aggregation diseases, they do tend to form aggregates on storage. There is thus a need to fine-tune peptide chaperones to increase their solubility, pharmacokinetics, and biological efficacy.This review summarizes the properties and the potential therapeutic roles of mini-chaperones in protein aggregation diseases and highlights some of the refinements needed to increase the stability and biological efficacy of mini-chaperones while maintaining or enhancing their chaperone-like activity against precipitation of unfolding proteins.Mini-chaperones suppress the aggregation of proteins, block amyloid fibril formation, stabilize mutant proteins, sequester metal ions, and exhibit antiapoptotic properties. Much work must be done to fine-tune mini-chaperones and increase their stability and biological efficacy. Peptide chaperones could have a great therapeutic value in diseases associated with protein aggregation and apoptosis.Accumulation of misfolded proteins is a primary cause for many age-related diseases, including cataract, macular degeneration, and various neurological diseases. Stabilization of native proteins is a logical therapeutic approach for such diseases. Mini-chaperones, with their inherent antiaggregation and antiapoptotic properties, may represent an effective therapeutic molecule to prevent the cascade of protein conformational disorders. Future studies will further uncover the therapeutic potential of mini-chaperones. This article is part of a Special Issue entitled Crystallin Biochemistry in Health and Disease.

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Biophysical Insights into Implications of PEG-400 on the ?-Crystallin Structure: Multispectroscopic and Microscopic Approach.

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Biophysical Insights into Implications of PEG-400 on the α-Crystallin Structure: Multispectroscopic and Microscopic Approach.

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