02326nas a2200181 4500008004100000022001400041245014600055210006900201260007100270300001400341490000700355520156100362100001801923700003301941700001801974700002301992856012902015 2011 eng d a0006-296000aSingle nucleotide polymorphism in transcobalamin II (15V) induces structural changes in the protein as revealed by molecular modeling studies0 aSingle nucleotide polymorphism in transcobalamin II 15V induces  a1155 16TH ST, NW, WASHINGTON, DC 20036 USAbAMER CHEMICAL SOCcMAR a1396-14020 v503 a

Cobalamin is an essential micronutrient in mammals. Deficiencies of this micronutrient have been implicated as risk factors for various complex diseases. Cobalamin is transported to the cells by the transport protein transcobalamin II (TCII), and hence genetic variations (like single nucleotide polymorphisms) in TCII could be perceived to affect the binding of cobalamin to TCII, thereby modulating the intracellular concentrations of cobalamin. To understand whether three nonsynonymous mutations in TCII (I5V, P241R, and R381Q) alter the structure of the protein which could potentially affect cobalamin binding, we performed molecular dynamics simulation in silico. Superimposition of active sites of the four simulated models (wild type and three variants) with the human TCII crystal structure revealed that the distance between the N epsilon nitrogen atom of His-173 and the cobalt ion of cobalamin deviated considerably in the I5V model as compared to wild type and other variants. His-173 directly coordinates with the cobalt ion of cobalamin. Further, from our dynamic cross-correlation and principal component analysis it appears that in the I5V model the beta-domain moves apart from the alpha-domain creating a wide gap between the two domains. This might facilitate the initial binding of cobalamin in the I5V model as cobalamin enters the binding site through the gap between the two domains. These observations were not found in the other variants. We thus speculate that binding of cobalamin will be more facile in the I5V variant.

1 aSilla, Yumnam1 aChandamouli, Balasubramanian1 aMaiti, Souvik1 aSengupta, Shantanu uhttps://library.ncl.res.in/content/single-nucleotide-polymorphism-transcobalamin-ii-15v-induces-structural-changes-protein-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

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.

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-002388nas 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-locked01918nas a2200265 4500008004100000022001400041245011100055210006900166260000900235300001200244490000700256520103600263653002101299653002001320653000801340653002601348653002001374100002301394700002201417700001901439700002001458700001801478700002401496856013201520 2018 eng d a1860-717900aSuperior HIV-1 TAR binders with conformationally constrained R52 arginine mimics in the Tat(48-57) peptide0 aSuperior HIV1 TAR binders with conformationally constrained R52  cFEB  a220-2260 v133 a

We report a 100-fold increase in binding affinity of the Tat(48-57) peptide to HIV-1 transcriptional activator-responsive element (TAR) RNA by replacing Arg52, an essential and critical residue for Tat's specific binding, with (2S,4S)-4-guanidinoproline. The resulting Tat1M peptide is a far superior binder than Tat1M, a peptide containing another conformationally constrained arginine mimic, (2S,4S)-4-amino-N-(3-guanidinopropyl)proline, or even the control Tat peptide (CtrlTat) itself. Our observations are supported by circular dichroism (CD), isothermal titration calorimetry (ITC), gel electrophoresis and UV spectroscopy studies. Molecular dynamics simulations suggest increased interactions between the more compact Tat1M and TAR RNA, relative to CtrlTat. The CD signature of the RNA itself remains largely unchanged upon binding of the peptides. The Tat mimetics further have better cell uptake properties than the control Tat peptide, thus increasing their potential application as specific TAR-binding molecules.

10aantiviral agents10aarginine mimics10aRNA10aTat peptide analogues10aTat-TAR binding1 aBhosle, Govind, S.1 aKharche, Shalmali1 aKumar, Santosh1 aSengupta, Durba1 aMaiti, Souvik1 aFernandes, Moneesha uhttps://library.ncl.res.in/content/superior-hiv-1-tar-binders-conformationally-constrained-r52-arginine-mimics-tat48-57-peptide