01692nas a2200289 4500008004100000022001500041245009900056210006900155260000800224300001600232490000700248520073200255100003200987700002101019700002301040700002201063700002001085700001601105700002601121700002201147700002301169700002501192700002201217700001901239700002301258856012101281 2018 eng d a 1433-785100aFrom a helix to a small cycle: metadynamics-inspired alpha v beta 6 integrin selective ligands0 aFrom a helix to a small cycle metadynamicsinspired alpha v beta  cOCT a14645-146490 v573 aThe RGD-recognizing alpha v beta 6 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 alpha v beta 6 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 alpha v beta 6-specific small peptides or even peptidomimetics. In vivo PET imaging studies demonstrated the potential use of 6 for medical applications.1 aDi Leva, Francesco, Saverio1 aTomassi, Stefano1 aDi Maro, Salvatore1 aReichart, Florian1 aNotni, Johannes1 aDangi, Abha1 aMarelli, Udaya, Kiran1 aBrancaccio, Diego1 aMerlino, Francesco1 aWester, Hans-Juergen1 aNovellino, Ettore1 aKessler, Horst1 aMarinelli, Luciana uhttps://library.ncl.res.in/content/helix-small-cycle-metadynamics-inspired-alpha-v-beta-6-integrin-selective-ligands01662nas a2200241 4500008004100000022001400041245006200055210006200117260000800179300001000187490000700197520088100204100002901085700003401114700002001148700002801168700002801196700001601224700002601240700002601266700003601292856009201328 2020 eng d a2045-232200aEGCG impedes human Tau aggregation and interacts with Tau0 aEGCG impedes human Tau aggregation and interacts with Tau cJUL a125790 v103 a

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 mu M.

1 aSonawane, Shweta, Kishor1 aChidambaram, Hariharakrishnan1 aBoral, Debjyoti1 aGorantla, Nalini, Vijay1 aBalmik, Abhishek, Ankur1 aDangi, Abha1 aRamasamy, Sureshkumar1 aMarelli, Udaya, Kiran1 aChinnathambi, Subashchandrabose uhttps://library.ncl.res.in/content/egcg-impedes-human-tau-aggregation-and-interacts-tau01822nas a2200193 4500008004100000022001400041245006400055210006400119260000900183300001400192490000700206520118600213100002801399700003401427700001601461700002601477700003601503856008901539 2020 eng d a0006-296000aHDAC6 ZnF UBP as the modifier of tau structure and function0 aHDAC6 ZnF UBP as the modifier of tau structure and function cDEC  a4546-45620 v593 a

Histone deacetylase 6 is a class H histone deacetylase primarily present in the cytoplasm and involved in the regulation of various cellular functions. It consists of two catalytic deacetylase domains and a unique zinc finger ubiquitin binding protein domain, which sets it apart from other HDACs. HDAC6 is known to regulate cellular activities by modifying the function of microtubules, HSP90, and cortactin through deacetylation. Apart from the catalytic activity of HDAC6, it interacts with other proteins through either the SE14 domain or the ZnF UBP domain to modulate their functions. Here, we have studied the role of the HDAC6 ZnF UBP domain as a modifier of Tau aggregation by its direct interaction with the polyproline region/repeat region of Tau. Interaction of HDAC6 ZnF UBP with Tau was found to reduce the propensity of Tau to self-aggregate and to disaggregate preformed aggregates in a concentration-dependent manner and also bring about the conformational changes in Tau protein. The interaction of HDAC6 ZnF UBP with Tau results in its degradation, suggesting either proteolytic activity of HDAC6 ZnF UBP or its role in enhancing autoproteolysis of Tau.

1 aBalmik, Abhishek, Ankur1 aChidambaram, Hariharakrishnan1 aDangi, Abha1 aMarelli, Udaya, Kiran1 aChinnathambi, Subashchandrabose uhttps://library.ncl.res.in/content/hdac6-znf-ubp-modifier-tau-structure-and-function02066nas a2200277 4500008004100000022001400041245010400055210006900159260000800228300001100236490000900247520113900256653002401395653001901419653001401438653002901452653001601481653001601497100002801513700001601541700001601557700002801573700002601601700003601627856012501663 2020 eng d a0304-416500aMelatonin interacts with repeat domain of Tau to mediate disaggregation of paired helical filaments0 aMelatonin interacts with repeat domain of Tau to mediate disaggr cMAR a1294670 v18643 a

Tau is the major neuronal protein involved in the stabilization of microtubule assembly. In Alzheimer's disease, Tau self-assembles to form intracellular protein aggregates which are toxic to cells. Various methods have been tried and tested to restrain the aggregation of Tau. Most of the agents tested for this purpose have limitations in their effectiveness and availability to neuronal cells. We have tested melatonin, a neurohormone secreted by pineal gland and a well-known anti-oxidant, for its ability to interact with the repeat domain of Tau using ITC and NMR. In aggregation inhibition and disaggregation studies of repeat Tau, melatonin was found to modulate the aggregation propensity of repeat Tau at a concentration of 5000 mu M and was more effective in dissolving preformed aggregates rather than acting as an aggregation inhibitor. However, there were no major conformational changes in Tau in presence of melatonin as observed by CD spectroscopy. On the basis of our findings, we are proposing a mechanism by which melatonin can interact with the repeat domain of Tau and exhibit its disaggregation effect.

10aAlzheimer's disease10aDisaggregation10amelatonin10aPaired helical filaments10atau protein10aTauopathies1 aBalmik, Abhishek, Ankur1 aDas, Rashmi1 aDangi, Abha1 aGorantla, Nalini, Vijay1 aMarelli, Udaya, Kiran1 aChinnathambi, Subashchandrabose uhttps://library.ncl.res.in/content/melatonin-interacts-repeat-domain-tau-mediate-disaggregation-paired-helical-filaments01734nas a2200277 4500008004100000022001400041245008800055210006900143260000800212300001100220490000700231520084400238653002101082653001601103653001401119653002301133100002401156700002201180700002501202700002201227700001601249700002601265700001901291700002801310856011801338 2020 eng d a0960-894X00aNovel cilengitide-based cyclic RGD peptides as alpha nu beta(3) integrin inhibitors0 aNovel cilengitidebased cyclic RGD peptides as alpha nu beta3 int cAPR a1270390 v303 a

In this letter, we report a series of five new RGD-containing cyclic peptides as potent inhibitors to alpha nu beta(3) integrin protein. We have incorporated various unnatural lipophilic amino acids into the cyclic RGD framework of cilengitide, which is selective for alpha nu beta(3) integrin. All the newly synthesized cyclic peptides were evaluated in vitro solid phase binding assay and investigated for their binding behaviour towards integrin subtypes. All the cyclic peptides were synthesized in excellent yield following solution-phase coupling strategy. The cyclic RGD peptides 1a-e exhibited IC50 of 9.9, 5.5, 72, 11 and 3.3 nM, respectively, towards a alpha nu beta(3) integrin protein. This finding offers further opportunities for the introduction unusual amino acids into the cyclic peptide framework of cilengitide.

10aAnticancer drugs10aCilengitide10aIntegrins10aRGD cyclicpeptides1 aMeena, Chhuttan, L.1 aSingh, Dharmendra1 aWeinmueller, Michael1 aReichart, Florian1 aDangi, Abha1 aMarelli, Udaya, Kiran1 aZahler, Stefan1 aSanjayan, Gangadhar, J. uhttps://library.ncl.res.in/content/novel-cilengitide-based-cyclic-rgd-peptides-alpha-nu-beta3-integrin-inhibitors01562nas a2200205 4500008004100000245010000041210006900141260000800210300001600218490000700234520079900241100001601040700002801056700002901084700002801113700002901141700003601170700002601206856012401232 2020 eng d00aResidue-based propensity of aggregation in the Tau amyloidogenic hexapeptides AcPHF6*and AcPHF60 aResiduebased propensity of aggregation in the Tau amyloidogenic  cJUL a27331-273350 v103 a

In Alzheimer's disease and related tauopathies, the aggregation of microtubule-associated protein, Tau, into fibrils occursviathe interaction of two hexapeptide motifs PHF*(275)VQIINK(280)and PHF(306)VQIVYK(311)as beta-sheets. To understand the role of the constituent amino acids of PHF and PHF* in the aggregation, a set of 12 alanine mutant peptides was synthesized by replacing each amino acid in PHF and PHF* with alanine and they were characterized by nuclear magnetic resonance (NMR) spectroscopy, circular dichroism (CD), transmission electron microscopy (TEM) and ThS/ANS fluorescence assay. Our studies show that while the aggregation was suppressed in most of the alanine mutant peptides, replacement of glutamine by alanine in both PHF and PHF* enhanced the fibrillization.

1 aDangi, Abha1 aBalmik, Abhishek, Ankur1 aGhorpade, Archana, Kisan1 aGorantla, Nalini, Vijay1 aSonawane, Shweta, Kishor1 aChinnathambi, Subashchandrabose1 aMarelli, Udaya, Kiran uhttps://library.ncl.res.in/content/residue-based-propensity-aggregation-tau-amyloidogenic-hexapeptides-acphf6and-acphf602240nas a2200205 4500008004100000022001400041245015900055210006900214260000800283300001400291490000700305520147500312100001601787700001801803700001901821700001901840700003001859700002601889856011901915 2023 eng d a1477-052000aTotal synthesis, structure elucidation and expanded bioactivity of icosalide A: effect of lipophilicity and ester to amide substitution on its bioactivity0 aTotal synthesis structure elucidation and expanded bioactivity o cJUL a5725-57310 v213 a

The first total synthesis of icosalide A, an antibacterial depsipeptide that is unique in that it contains two lipophilic beta-hydroxy acids, has been achieved by following Fmoc solid-phase peptide synthesis in combination with solution-phase synthesis. The ambiguity in the absolute stereochemistry of icosalide A has been resolved by synthesizing the reported structures and other relevant diastereomers of icosalides and comparing their NMR data. NMR-based structure elucidation of icosalide A revealed a well-folded structure with cross-strand hydrogen bonds similar to the anti-parallel beta-sheet conformation in peptides and displayed a synergistic juxtaposition of the aliphatic sidechains. 12 analogues of icosalide A were synthesized by varying the constituent lipophilic beta-hydroxy acid residues, and their biological activities against Bacillus thuringiensis and Paenibacillus dendritiformis were explored. Most of these icosalide analogues showed an MIC of 12.5 & mu;g mL(-1) against both bacteria. Swarming inhibition by icosalides was least in B. thuringiensis (8.3%) compared to that in P. dendritiformis (33%). Furthermore, this is the first report of icosalides showing assured inhibitory action (MIC between 2 and 10 & mu;g mL(-1)) against the active stage of Mycobacterium tuberculosis and cancer cell lines such as HeLa and ThP1. This study could help optimize icosalides for anti-TB, antibacterial, and anti-cancer activities.

1 aDangi, Abha1 aPande, Bharat1 aAgrawal, Sonia1 aSarkar, Dhiman1 aVamkudoth, Koteswara, Rao1 aMarelli, Udaya, Kiran uhttps://library.ncl.res.in/content/total-synthesis-structure-elucidation-and-expanded-bioactivity-icosalide-effect02282nas a2200241 4500008004100000022001400041245010000055210006900155260000800224300001100232490000800243520144900251653002001700653003801720653002501758653001701783653002001800100001601820700002001836700003601856700002601892856012201918 2024 eng d a0045-206800aMacrocyclic peptides derived from AcPHF6*and AcPHF6 to selectively modulate the Tau aggregation0 aMacrocyclic peptides derived from AcPHF6and AcPHF6 to selectivel cOCT a1076250 v1513 a

Ten macrocyclic peptides, each comprising 14 amino acids, were designed and synthesized based on the Tau aggregation model hexapeptides AcPHF6* and AcPHF6. The design took into account the aggregation tendencies of each residue in AcPHF6* and AcPHF6, their aggregation models, while employing peptide-based structural design principles including N-methylation to promote turns and to block hydrogen bond propagation and elongation of the aggregation chain. NMR analysis supported that all these peptides adopted an antiparallel beta-sheet conformation. Self-aggregation studies characterized the aggregation properties of these peptides, identifying two peptides with the highest (P3) and lowest (P8) aggregation tendencies. In cross-aggregation studies with the parent peptides AcPHF6* and AcPHF6, P3 and P8 were found to promote and reduce aggregation, respectively. Furthermore, P3 and P8 demonstrated an enhancement and diminution effect on the aggregation of K18wt, indicating their capacity to modulate aggregation even at the macromolecular level. Thus, the two simple peptides, P3 and P8 selectively exhibit pro- or anti-aggregation effects on PHF peptides and Tau. This study, has thus developed structurally well-defined non-complex peptides, derived from AcPHF6* and AcPHF6, to modulate Tau aggregation as desired, offering applications in Tau model studies and the development of Tau aggregation inhibitors or promoters.

10aCyclic peptides10aPeptide -based drug design (PBDD)10aPeptide conformation10aPHF peptides10aTau Aggregation1 aDangi, Abha1 aQureshi, Tazeen1 aChinnathambi, Subashchandrabose1 aMarelli, Udaya, Kiran uhttps://library.ncl.res.in/content/macrocyclic-peptides-derived-acphf6and-acphf6-selectively-modulate-tau-aggregation