02140nas a2200217 4500008004100000022001400041245007400055210006900129260011000198300001600308490000600324520132500330100002201655700002401677700002301701700002401724700002101748700002501769700002401794856010401818 2015 eng d a2046-206900aN-(3-Aminoalkyl)proline derivatives with potent antigycation activity0 aN3Aminoalkylproline derivatives with potent antigycation activit aTHOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLANDbROYAL SOC CHEMISTRYcSEP a77332-773400 v53 a

The importance of amino acids in the therapy of conditions such as renal failure, neurological disorders and congenital defects has been documented. Some amino acids such as lysine and glycine have also been reported to have antiglycating activity. Herein we report the synthesis of a new series of N-(3-aminoalkyl)proline derivatives which are non-natural in nature. The compounds were unambiguously characterized by NMR, mass and IR spectroscopy. Their in vitro antiglycation activity was studied by circular dichroism and fluorescence spectrometry. The mechanism of action was also studied and found to take place by inhibition of Amadori product formation. The inhibition of AGE formation was further confirmed by western blot and LC-MS/MS analyses and the IC50 values of the potent compounds were determined. Compounds containing hydroxyl substituents at C4 were found to have superior antiglycation properties than those containing azide substituents at the same position. The compounds were additionally found to possess good anti-oxidant properties, which could lead to further reduction in AGE formation. Moreover, the title compounds were found to have low cytotoxicity in mammalian cells, another important attribute. Thus, the title compounds represent a novel promising class of antiglycating agents.

1 aChilukuri, Harsha1 aKolekar, Yogesh, M.1 aBhosle, Govind, S.1 aGodbole, Rashmi, K.1 aKazi, Rubina, S.1 aKulkarni, Mahesh, J.1 aFernandes, Moneesha uhttps://library.ncl.res.in/content/n-3-aminoalkylproline-derivatives-potent-antigycation-activity-001320nas a2200205 4500008004100000022001400041245012500055210006900180260000900249300001400258490000700272520056800279653001800847653003000865653002000895653002300915100002300938700002400961856012900985 2017 eng d a1860-717900a(R-X-R)(4)-Motif peptides containing conformationally constrained cyclohexane-derived spacers: effect on cellular uptake0 aRXR4Motif peptides containing conformationally constrained cyclo cNOV  a1743-17470 v123 a

Arginine-rich peptides having the (R-X-R) n motif are among the most effective cell-penetrating peptides (CPPs). Herein we report a several-fold increase in the efficacy of such CPPs if the linear flexible spacer (-X-) in the (R-X-R) motif is replaced by constrained cyclic 1,4-substituted-cyclohexane-derived spacers. Internalization of these oligomers in mammalian cell lines was found to be an energy-dependent process. Incorporation of these constrained, non-proteinogenic amino acid spacers in the CPPs is shown to enhance their proteolytic stability.

10a(R-X-R)-motif10acell-penetrating peptides10acellular uptake10aprotease stability1 aBhosle, Govind, S.1 aFernandes, Moneesha uhttps://library.ncl.res.in/content/r-x-r4-motif-peptides-containing-conformationally-constrained-cyclohexane-derived-spacers01695nas a2200181 4500008004100000245008700041210006900128260000800197300001200205490000800217520106500225100002301290700001901313700002101332700001901353700002401372856011701396 2018 eng d00aAntibacterial and anti-TB tat-peptidomimetics with improved efficacy and half-life0 aAntibacterial and antiTB tatpeptidomimetics with improved effica cMAY a358-3690 v1523 aNon-natural antimicrobial peptides are ideal as next-generation antibiotics because of their ability to circumvent the problems of drug resistance and in vivo instability. We report novel all-alpha- and alpha,gamma-mixed Tat peptide analogues as potential antibacterial and anti-TB agents. These peptides have broad spectrum antibacterial activities against Gram-positive (MICs 0.61 +/- 0.03 to 1.35 +/- 0.21 mu M with the peptide gamma TatM4) and Gram-negative (MICs 0.71 +/- 0.005 to 1.26 +/- 0.02 M with gamma TatM4) bacteria and are also effective against active and dormant forms of Mycobacterium tuberculosis, including strains that are resistant to rifampicin and isoniazid. The introduction of the non-natural amino acids of the study in the Tat peptide analogues results in increased resistance to degradation by proteolysis, significantly increasing their half-life. The peptides appear to inhibit bacteria by a membrane disruption mechanism, and have only a low cytotoxic effect on mammalian cells. (C) 2018 Elsevier Masson SAS. All rights reserved.1 aBhosle, Govind, S.1 aNawale, Laxman1 aYeware, Amar, M.1 aSarkar, Dhiman1 aFernandes, Moneesha uhttps://library.ncl.res.in/content/antibacterial-and-anti-tb-tat-peptidomimetics-improved-efficacy-and-half-life01918nas 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