The RGD-recognizing αvβ6 integrin has only recently emerged as a major target for cancer diagnosis and therapy. Thus, the development of selective, low-molecular-weight ligands of this receptor is still in great demand. Here, a metadynamics-driven design strategy allowed us to successfully convert a helical nonapeptide into a cyclic pentapeptide (6) showing remarkable potency and αvβ6 specificity. NMR and docking studies elucidated the reasons for the high affinity and selectivity of this compound, setting the ground for the rational design of new αvβ6-specific small peptides or even peptidomimetics. In vivo PET imaging studies demonstrated the potential use of 6 for medical applications.
Tau aggregation and accumulation is a key event in the pathogenesis of Alzheimer's disease. Inhibition of Tau aggregation is therefore a potential therapeutic strategy to ameliorate the disease. Phytochemicals are being highlighted as potential aggregation inhibitors. Epigallocatechin-3-gallate (EGCG) is an active phytochemical of green tea that has shown its potency against various diseases including aggregation inhibition of repeat Tau. The potency of EGCG in altering the PHF assembly of full-length human Tau has not been fully explored. By various biophysical and biochemical analyses like ThS fluorescence assay, MALDI-TOF analysis and Isothermal Titration Calorimetry, we demonstrate dual effect of EGCG on aggregation inhibition and disassembly of full-length Tau and their binding affinity. The IC50 for Tau aggregation by EGCG was found to be 64.2 μM. Abbreviations EGCG Epigallocatechin-3-gallate AD Alzheimer's disease Aβ Amyloid-β IAPP Islet amyloid polypeptide ITC Isothermal titration calorimetry TEM Transmission electron microscopy SEC Size exclusion chromatography MTT 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide ThS Thioflavin S ANS 8-Anilino-1-naphthalenesulfonic acid ammonium salt The direct causal relationship between neurodegenerative disorders and protein misfolding has been debatable over years 1-3. The recent advances in studies of misfolded proteins to some extent have shed the light upon the cause-effect interdependence of proteins and diseases 4. Neurodegenerative diseases are diverse in nature at physiological as well as molecular level. For example, the misfolded proteins involved in Alzheimer's disease (AD) are amyloid-β (Aβ) and Tau (Fig. 1A) whereas 5 ; α-Synuclein is a key player in Parkinson's disease. AD is phenotypically characterized by gradual memory loss due to neuronal death 6. The molecular pathology involves abnormal accumulation of Aβ plaques 7 in the extracellular milieu and cytoplasmic Tau tangles 8,9. Tau aggregation increases load on clearance machinery of neurons, which finally collapses, and results in neuronal death 10,11. The physiological function of Tau is to bind microtubules and stabilize them thus aiding in neuronal functioning 12,13. Tau aggregates abnormally due to multiple factors-like mutations, aberrant post-translational modifications, oxidative stress etc. 14-16. Abnormal phosphorylation of Tau is one of the key factors implied in its aggregation 17,18. The factors leading to Tau aggregation have directed the researchers to design and develop the therapeutics against Tau aggregation and AD. Several classes of compounds showing potency in inhibiting Tau aggregation include phenothiazines 19,20 , anthraquinones 21 , porphyrins, aminothienopyridazines 22 , natural compounds (polyphenols 23 , secondary metabolites 24 , curcumin 25 , Oleocanthal 26 etc.). The phenothiazine compounds inhibit Tau-Tau (repeat domain) binding thus preventing Tau aggregation. These compounds have
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