01335nas a2200193   4500008004100000022001400041245010900055210006900164260011000233300001400343490000700357520055400364100001700918700001800935700002400953700001700977700001800994856012901012       2014                        eng d  a1359-734500aAnti-cancer therapeutic potential of quinazoline based small molecules via global upregulation of miRNAs0 aAnticancer therapeutic potential of quinazoline based small mole  aTHOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLANDbROYAL SOC CHEMISTRYcMAR  a4639-46420 v503 a<p>Three quinazoline based small molecules showed global upregulation of miRNA expression with a selective enrichment of tumor suppressor miRNAs. The target genes of the upregulated miRNAs were predicted to be enriched for apoptotic pathways. Apoptotic induction following treatment with quinazoline compounds was confirmed by in cellulo studies. Thus, these small molecules having the core structural moiety (2,4-diphenyl-quinazoline) can be used as scaffolds to design activators of miRNA expression paving the way for novel anti-cancer drugs.</p>1 aNahar, Smita1 aBose, Debojit1 aPanja, Sumit, Kumar1 aSaha, Satyen1 aMaiti, Souvik  uhttps://library.ncl.res.in/content/anti-cancer-therapeutic-potential-quinazoline-based-small-molecules-global-upregulation-001217nas a2200193   4500008004100000022001400041245013800055210006900193260011000262300001400372490000700386520040200393100001700795700002000812700001700832700001800849700002600867856013000893       2015                        eng d  a1359-734500aBeta, gamma-Bis-substituted PNA with configurational and conformational switch: preferred binding to cDNA/RNA and cell-uptake studies0 aBeta gammaBissubstituted PNA with configurational and conformati  aTHOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLANDbROYAL SOC CHEMISTRYcMAR  a7693-76960 v513 a<p>(S,S)- and (R,R)-beta,gamma-Bis-substituted PNAs were synthesized from the C-2 symmetric vicinal diamine system embedded in 1,4 dihydroxybutane and 1,4-dimethoxybutane scaffolds. (R,R)-beta,gamma-Bis-methoxymethyl-PNA derived from D-tartaric acid was found to be in the right configuration and conformation to be an excellent mimic of PNA, endowed with superior ability to enter into cells.</p>1 aBose, Tanaya1 aBanerjee, Anjan1 aNahar, Smita1 aMaiti, Souvik1 aKumar, Vaijayanti, A.  uhttps://library.ncl.res.in/content/beta-gamma-bis-substituted-pna-configurational-and-conformational-switch-preferred-binding01959nas a2200193   4500008004100000022001400041245014100055210006900196260008800265300001200353490000700365520116900372100001701541700001801558700001501576700003101591700001801622856012501640       2015                        eng d  a2159-333700aCyclic cationic peptides containing sugar amino acids selectively distinguishes and inhibits maturation of pre-mirnas of the same family0 aCyclic cationic peptides containing sugar amino acids selectivel  a140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USAbMARY ANN LIEBERT, INCcDEC  a323-3290 v253 a<p>The discovery of microRNAs (miRNAs) has added a new dimension to the gene regulatory networks, making aberrantly expressed miRNAs as therapeutically important targets. Small molecules that can selectively target and modulate miRNA levels can thus serve as lead structures. Cationic cyclic peptides containing sugar amino acids represent a new class of small molecules that can target miRNA selectively. Upon treatment of these small molecules in breast cancer cell line, we profiled 96 therapeutically important miRNAs associated with cancer and observed that these peptides can selectively target paralogous miRNAs of the same seed family. This selective inhibition is of prime significance in cases when miRNAs of the same family have tissue-specific expression and perform different functions. During these conditions, targeting an entire miRNA family could lead to undesired adverse effects. The selective targeting is attributable to the difference in the three-dimensional structures of precursor miRNAs. Hence, the core structure of these peptides can be used as a scaffold for designing more potent inhibitors of miRNA maturation and hence function.</p>1 aNahar, Smita1 aBose, Debojit1 aPal, Sudip1 aChakraborty, Tushar, Kanti1 aMaiti, Souvik  uhttps://library.ncl.res.in/content/cyclic-cationic-peptides-containing-sugar-amino-acids-selectively-distinguishes-and-002675nas a2200169   4500008004100000022001400041245007100055210006900126260011000195300001200305490000700317520201100324100003102335700001702366700001802383856010402401       2015                        eng d  a1359-734500aNonconventional chemical inhibitors of microRNA: therapeutic scope0 aNonconventional chemical inhibitors of microRNA therapeutic scop  aTHOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLANDbROYAL SOC CHEMISTRYcOCT  a820-8310 v513 a<p>MicroRNAs (miRNAs) are a class of genomically encoded small RNA molecules (similar to 22nts in length), which regulate gene expression post transcriptionally. The term microRNA or miRNA was coined in 2001, and research in the past decade has shed light on their widespread occurrence, evolutionary conservation and tissue specific functions. It is estimated that they modulate the gene expression of approximately 60% of the mammalian genes by regulating the levels of target mRNAs to which they can bind on the basis of sequence complementarities. miRNAs are produced in a well coordinated series of steps from being transcribed in the nucleus to exerting their function in the cytoplasm. miRNAs are now implicated in diverse biological phenomena ranging from development to stress response which makes miRNAs one of the central regulatory molecules which modulate information flow along the central dogma of gene expression. More importantly, like any regulatory molecule, deregulation of miRNAs is causally associated with several diseases (mainly cancer) and is directly involved in a variety of pathophysiologies owing to their aberrant expression. Thus, modulation of miRNA levels is of prime therapeutic importance. Conventional methods of miRNA knockdown using chemically modified antisense-oligonucleotides have been explored extensively but face the challenges of modes of delivery, biostability and biodistribution. This calls for the development of more alternative and non-conventional methods to target miRNA. Small molecules targeting RNA chemical and structural space provide one such timely opportunity. In this article we first provide a brief overview of miRNA biogenesis and its disease associations. We then summarize the major developments in conventional oligonucleotide based approaches to miRNA knockdown and its status. We then focus on the more non-conventional methods like oligonucleotide enzymes and small molecules and provide an outlook on the future of such methods.</p>1 aJayaraj, Gopal, Gunanathan1 aNahar, Smita1 aMaiti, Souvik  uhttps://library.ncl.res.in/content/nonconventional-chemical-inhibitors-microrna-therapeutic-scope-001803nas a2200193   4500008004100000022001400041245007300055210006900128260011000197300001400307490000600321520109200327100001701419700001801436700001501454700001801469700001801487856010401505       2015                        eng d  a2041-652000aPotent inhibition of miR-27a by neomycin-bisbenzimidazole conjugates0 aPotent inhibition of miR27a by neomycinbisbenzimidazole conjugat  aTHOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLANDbROYAL SOC CHEMISTRYcJUL  a5837-58460 v63 a<p>miRNAs are important components of regulatory networks that control gene expression and have implications in various diseases including cancer. Targeting oncogenic miRNAs with small molecules is currently being explored to develop cancer therapeutics. Here, we report the development of dual binding neomycin-bisbenzimidazole conjugates that target oncogenic miR-27a with high affinity (K-a = 1.2 to 7.4 x 10(8) M-1). These conjugates bring significant reduction (similar to 65% at 5 mu M) in mature miRNA levels and penetrate easily in the cells where they localise both in the cytoplasm and the nucleus. Cell cycle analysis showed significant increase in the G0/G1 phase (similar to 15%) and decrease in the S phase (similar to 7%) upon treatment with neomycin-bisbenzimidazole conjugates, suggesting inhibition of cell proliferation. Using the conjugation approach, we show that moderately binding ligands can be covalently combined into high affinity binders. This study also highlights the role of linker optimization in designing high affinity ligands for miR-27a targeting.</p>1 aNahar, Smita1 aRanjan, Nihar1 aRay, Arjun1 aArya, Dev, P.1 aMaiti, Souvik  uhttps://library.ncl.res.in/content/potent-inhibition-mir-27a-neomycin-bisbenzimidazole-conjugates-001733nas a2200205   4500008004100000022001400041245006900055210006800124260007200192300001400264490000700278520102700285100001801312700001701330700002301347700001501370700002401385700001801409856010001427       2015                        eng d  a0305-104800aSelective inhibition of miR-21 by phage display screened peptide0 aSelective inhibition of miR21 by phage display screened peptide  aGREAT CLARENDON ST, OXFORD OX2 6DP, ENGLANDbOXFORD UNIV PRESScAPR  a4342-43520 v433 a<p>miRNAs are nodal regulators of gene expression and deregulation of miRNAs is causally associated with different diseases, including cancer. Modulation of miRNA expression is thus of therapeutic importance. Small molecules are currently being explored for their potential to downregulate miRNAs. Peptides have shown to have better potency and selectivity toward their targets but their potential in targeting and modulating miRNAs remain unexplored. Herein, using phage display we found a very selective peptide against pre-miR-21. Interestingly, the peptide has the potential to downregulate miR-21, by binding to pre-miR-21 and hindering Dicer processing. It is selective towards miR-21 inside the cell. By antagonising miR-21 function, the peptide is able to increase the expression of its target proteins and thereby increase apoptosis and suppress cell proliferation, invasion and migration. This peptide can further be explored for its anti-cancer activity in vivo and may be even extended to clinical studies.</p>1 aBose, Debojit1 aNahar, Smita1 aRai, Manish, Kumar1 aRay, Arjun1 aChakraborty, Kausik1 aMaiti, Souvik  uhttps://library.ncl.res.in/content/selective-inhibition-mir-21-phage-display-screened-peptide-001541nas a2200241   4500008004100000022001400041245013200055210006900187260000800256300001200264490000700276520072300283653001501006653001101021653001301032653001801045653002101063100001701084700002201101700002601123700001801149856013201167       2016                        eng d  a2159-333700aInhibition of miR-21 by 3 `/5 `-serinyl-capped 2 `-O-Methyl RNA Interspersed with 2 `-O-(2-Amino-3-Methoxypropyl) uridine units0 aInhibition of miR21 by 3 5 serinylcapped 2 OMethyl RNA Intersper  cOCT  a327-3340 v263 a<p>miRNAs are highly conserved class of small ncRNAs whose involvement in human pathophysiologies is extensively investigated. MiR-21 is a well established oncogenic miRNA whose deregulation plays a significant role in onset and progression of cancer. The need of novel approaches to downregulate miR-21 is rapidly expanding. Potent inhibition of miR-21 is achieved by chemically modified 2-O-methyl RNA oligonucleotide. The serinol capping at 3 and 5ends and the interspersed 2-O-(R-2-amino-3-methoxypropyl) uridine units enhance the nuclease resistance and efficacy of 2-O-methyl RNA for the inhibition of miR-21. This represents a simple and novel modification for developing oligonucleotide-based therapeutics.</p>10aantagomirs10acancer10amicroRNA10anoncoding RNA10aoligonucleotides1 aNahar, Smita1 aKotikam, Venubabu1 aKumar, Vaijayanti, A.1 aMaiti, Souvik  uhttps://library.ncl.res.in/content/inhibition-mir-21-3-5-serinyl-capped-2-o-methyl-rna-interspersed-2-o-2-amino-3-methoxypropyl02388nas a2200205   4500008004100000245014100041210006900182260000800251300001400259490000700273520164000280100001701920700001801937700002301955700002001978700002001998700001902018700001802037856012702055       2016                        eng d00aSystematic evaluation of biophysical and functional characteristics of selenomethylene-locked nucleic acid-mediated inhibition of miR-210 aSystematic evaluation of biophysical and functional characterist  cDEC  a7023-70320 v553 amiRNAs constitute an important layer of gene regulation mediated by sequence-specific targeting of mRNAs. Aberrant expression of miRNAs contributes to a host of pathological states. Promoting cancer, miR-21 is upregulated in variety of cancers and promotes tumor progresion by suppressing a network of tumor suppressor genes. Here we describe a novel class of bicyclic RNA analogues, selenomethylene-locked nucleic acid (SeLNA), that display high affinity, improved metabolic stability, and increased potency for miR-21 inhibition. The thermal stability (T-m) for duplexes was increased significantly with incorporation of SeLNA monomers as compared to that of the unmodified DNA RNA hybrid. A comprehensive thermodynamic profile obtained by isothermal titration calorimetry revealed a favorable increase in the enthalpy of hybridization for SeLNA containing DNA and target RNA heteroduplexes. SeLNA modifications displayed remarkable binding affinity for miR-21 target RNA with a K-a of <= 1.05 x 10(8) M-1. We also observed enhanced serum stability for SeLNA RNA duplexes with a half-life of <= 36 h. These in vitro results were well correlated with the antisense activity in cancer cells imparting up to similar to 91% inhibition of miR-21. The functional impact of SeLNA modifications on miR-21 inhibition was further gauged by investigating the migration and invasion characterisitics of cancer cells, which were drastically reduced to similar to 49 and similar to 55%, respectively, with SeLNA having four such modifications. Our findings demonstrate SeLNA as a promising candidate for therapeutics for disease associated miRNAs.1 aNahar, Smita1 aSingh, Amrita1 aMorihiro, Kunihiko1 aMoai, Yoshihiro1 aKodama, Tetsuya1 aObika, Satoshi1 aMaiti, Souvik  uhttps://library.ncl.res.in/content/systematic-evaluation-biophysical-and-functional-characteristics-selenomethylene-locked01757nas a2200229   4500008004100000022001400041245010000055210006900155260000800224300001400232490000700246520099300253100001701246700001801263700002001281700001601301700001801317700002301335700002701358700001801385856012401403       2018                        eng d  a1359-734500aG-quadruplex motif at the 3' end of sgRNAs improves CRISPR-Cas9 based genome editing efficiency0 aGquadruplex motif at the 3 end of sgRNAs improves CRISPRCas9 bas  cMAR  a2377-23800 v543 aOriginating as a component of prokaryotic adaptive immunity, the type II CRISPR/Cas9 system has been repurposed for targeted genome editing in various organisms. Although Cas9 can bind and cleave DNA efficiently under in vitro conditions, its activity inside a cell can vary dramatically between targets owing to differences between genomic loci and availability of enough Cas9/sgRNA (single guide RNA) complex molecules for cleavage. Most methods to improve CRISPR/Cas9 activity have so far relied on Cas9 protein engineering or base modifications in the sgRNA sequence. Here we demonstrate that a structure based rational design of sgRNAs can enhance the efficiency of Cas9 cleavage in vivo. By appending a naturally forming RNA G-quadruplex motif to the 3′ end of sgRNAs we can improve its stability and target cleavage efficiency in zebrafish embryos without inducing off-target activity, thereby underscoring its value in the design of better and optimized genome editing triggers.1 aNahar, Smita1 aSehgal, Paras1 aAzhar, Mohammad1 aRai, Manish1 aSingh, Amrita1 aSivasubbu, Sridhar1 aChakraborty, Debojyoti1 aMaiti, Souvik  uhttps://library.ncl.res.in/content/g-quadruplex-motif-3-end-sgrnas-improves-crispr-cas9-based-genome-editing-efficiency