The Lee and William Abramowitz
Novel HIV-1 Tat AntagonistsDesign, synthesis, structure and function of novel HIV-1 inhibitors, targeted against transcription transactivator protein (Tat)-aminoglycoside-arginine conjugates (AACs) are being studied with the aim of understanding the mechanisms of inhibition of the diversity functions of Tat protein, which might be critical for anti-AIDS strategies. This new class of components revealed antiviral activity in cell cultures and inhibited viral-host cell fusion, as well as binding to TAR-RNA (with G. Borkow, Kaplan Hospital and J. Este, Spain). Other anti-Tat functions in cell cultures and animal models are being studied in several medical centers in Europe, USA and Canada (with G. Melino, Italy, and J. Pelleier, Canada). As well, are animal models for Kaposis Sarcoma (an angio-proliferate disease associated with AIDS; with B. Ensoli, Italy). Moreover, our finding that AACs are better inhibitors of bacterial RRNase P compared to human RNase P activity validates the idea that bacterial RNase P-specific inhibitors could either be rationally designed or identified from a combinatorial library of small molecules (with V. Gopalan, USA).
The Role and Function of New Tetrahydropyrimidine Derivatives. In Vivo and In Vitro StudiesTwo tetrahydropyrimidine derivatives (THPs) were identified in actinomycin-producing streptomycetes and as a response to salt and heat stress. A novel protection mechanism of DNA-protein interaction, involving the THPs based on NMR and molecular biological techniques, was suggested. Structure, function and dymanics studies of DNA-THPs and the protection mechanism of DNA from heat and salt stress were studied. The use of THPs for low temperature cycled PCR was developed.
Biomedical Applications of NMR and Stable Isotopes in Brain ResearchThe impact of maternal diabetes on fetal and neonate brain metabolisms is investigated by 13C MRS and stable isotope techniques. Two hypotheses are examined: (1) whether the poorly controlled maternal diabetes has any effect on either maternal or fetal glucose metabolism, which may cause neurological complications in the neonate of the diabetic mother and (2) the effect of aggresive control of glucose concentration in the mother (by insulin administration) on fetal brain glucose metabolism.
Plausible structure of the TAR-RNA complex with NeoR. Specifically, the arginine on ring I conjugated via the aliphatic amine of neomycin B is positioned in the cavity formed by the bulge of TAR-RNA. The surface of TAR-RNA is colored white, except for the phosphate groups, which are red. The neomycin core of NeoR is shown in green and the arginine moieties are in yellow. The guanidino group of the arginine on ring I interacts with atoms N7 and O6 of guanine 26, whose surface is shown in magenta. The a-amino group interacts with the O2P atoms of guanines 21 and 36 of TAR-RNA. The structure of the TAR-RNA is based on the structure of the TAR-RNA-arginine complex (PDB code 1arj). The right panel is a ~90 degrees turn clockwise of the left panel.
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Kalinkovich A, Schjanovitz A, Lapid K, Berchanski A, Borkow G, Itkin T, Ludin A, Gur-Cohen S, Golan K, Kollet O, Ahrens K, Proksch E, Lapidot A, Fridkin M, Lapidot T, "A New Role For Beta-Defensins: Induction Of Rapid Mobilization Of Hematopoietic Progenitors Via Enhanced CXCR4 Signaling And CXCL12 Release", Journal of Clinical Immunology, 32, 97 (2012). [Read online]
Berchanski A, Kalinkovich A, Ludin A, Lapidot T, Lapidot A, "Insights into the mechanism of enhanced mobilization of hematopoietic progenitor cells and release of CXCL12 by a combination of AMD3100 and aminoglycoside-polyarginine conjugates", FEBS Journal, 278, 4150-4165 (2011). [Read online]
Berchanski A, Lapidot A, "Computer-based design of novel HIV-1 entry inhibitors: neomycin conjugated to arginine peptides at two specific sites", Journal of Molecular Modeling, 15, 281-294 (2009). [Read online]
Lapidot A, Peled A, Berchanski A, Pal B, Kollet O, Lapidot T, Borkow G, "NeoR6 inhibits HIV-1-CXCR4 interaction without affecting CXCL12 chemotaxis activity", Biochimica et Biophysica Acta, 1780, 914-920 (2008). [Read online]
Berchansky A, Lapidot A, "Bacterial RNase P RNA is a drug target for aminoglycoside-arginine conjugates", Bioconjugate Chemistry, 19, 1896-1906 (2008). [Read online]
Lapidot A, Berchanski A, Borkow G, "Insight into the mechanisms of aminoglycoside derivatives interaction with HIV-1 entry steps and viral gene transcription", FEBS Journal, 275, 5236-5257 (2008). [Read online]
Berchanski A, Lapidot A, "Prediction of HIV-1 entry inhibitors neomycin-arginine conjugates interaction with the CD4-gp120 binding site by molecular modeling and multistep docking procedure", Biochimica and Biophysica Acta: Biomembranes, 1768, 2107-2119 (2007). [Read online]
Hegde R, Borkow G, Berchanski A, Lapidot A "Structure-function relationship of novel X4 HIV-1 entry inhibitors - L- and D-arginine peptide-aminoglycoside conjugates", FEBS Journal, 274, 6523-6536 (2007). [Read online]
Lapidot A, Borkow G "Multi-targeting the entrance door to block HIV-1 by aminoglycoside-arginine conjugates (AACs)", Antiviral Research, 65, A47 (2005). [Read online]
G. Borkow and A. Lapidot, "Multi-targeting the entrance door to block HIV-1", Current Drug Targets --- Infectious Disorders, 5, 3-15 (2005). [Read online]
A. Lapidot and G. Borkow, "Aminoglycoside-Arginine conjugates: chemical barriers of HIV-1 entry", Antiviral Research A 34, 17 (2004).
A. Lapidot, V. Vijayabaskar, A. Litovchick, J. Yu, and T. L. James, "Structure-Activity Relationshipos of aminoglycoside-arginine conjugates that bind HIV-1 RNAs as determined by fluorescence and NMR spectroscopy." FEBS Letters 577, 414-421 (2004) [Read online]
G. Borkow, H. H. Lara, M. Ayash-Rashkovsky, E. Tavor, A. Lapidot, Z. Bentwich, and A. Honigman, Adenovirus Expressing a Bioluminescence Reporter Gene and cMAGI cell Assay for the Detection of HIV-1, Virus Genes 29, 257-265 (2004) [Read online]
G. Borkow, H. H. Lara, and A. Lapidot, Mutations in gp41 and gp120 of HIV-1 isolates resistant to hexa-arginine neomycin B conjugate, Biochem. Biophys. Res. Comm. 312, 1047-1052 (2003); [Read online].
G. Borkow, V. Vijayabaskar, H. H. Lara, A. Kalinkovich, and A. Lapidot, Structure-Activity relationship of neomycyn, paromomycin, and neamine-arginine conjugates, targeting HIV-1 gp120-CXCR4 binding step, Antiviral Research 60, 181-192 (2003); [Read online].
M.V.Catani, M.T.Corasaniti, M.Ranalli, D.Amantea, A.Litovchick, A.Lapidot and G.Melino, The Tat antagonist neomycin B hexa-arginine conjugate inhibits gp120-induced death of human neuroblastoma cells, J. Neurochem. 84, 1237-1245 (2003). [read online]
M. Carriere, V. Vijayabaskar, D. Applefield, I. Harvey, P. Garneau, J. Lorsch, A. Lapidot, and J. Pelletier, Inhibition of protein synthesis by aminoglycoside-arginine conjugates, RNA 8, 1267 (2002). [read online]
A.Lapidot, A.Litovchick, M.Eisenstein, A.Kalinkovich, G.Borkow, Neomycin B-arginine conjugate, a novel HIV-1 Tat antagonist: synthesis and anti-HIV activities, Antivir. Res. 53 (3): 26 Sp. Iss. (2002). [read online soon]
A.Lapidot, S.Haber, Effect of endogenous b-hydroxybutyrate on brain glucose metabolism in fetuses of diabetic rabbits, studied by 13C magnetic resonance spectroscopy, Developmental Brain Research 135, 87 (2002). [read online]
T. D. Eubank, R. Biswas, M. Jovanovic, A. Litovchick, A. Lapidot, and V. Gopalan, Inhibition of bacterial RNase P by aminoglycoside-arginine conjugates, FEBS Letters 517, 107 (2002). [read online]
C. Cabrera, A. Gutiérrez, J. Barretina, J. Blanco, A. Litovchick, A. Lapidot, B. Clotet, and J. A. Esté, Anti-HIV activity of a novel aminoglycoside-arginine conjugate, Antiviral Research 53, 1 (2002). [read online]
A. Litovchick, A. Lapidot, M. Eisenstein, A. Kalinkovich, and G. Borkow, Neomycin B - arginine conjugate, a novel HIV-1 tat antagonist: synthesis and anti-HIV activities, Biochemistry 40, 15612 (2001). [read online]
A. Lapidot and S. Haber, Energy fuel utilization by fetal versus young rabbit brain: a 13C NMR isotopomer analysis of [U-13C]glucose metabolites. Brain Res. 896 102, 2001.[read online]
A. Lapidot and S. Haber, Effect of endogenous beta-hydroxybutyrate on glucose metabolism in the diabetic rabbit brain: a 13C magnetic resonance spectroscopy study of [U-13C]glucose metabolites. J. Neurosci. Res. 64 207 (2001). [read online]
A. Litovchick and A. Lapidot, Novel HIV Tat antaganoists. Drug Dev. Res. 50, 502 (2000).[read online]
C. Cabrera, A. Gutierrez, J. Blanco, J. Barretina, A. Litovchick, A.Lapidot, A.G. Evdokimov, B. Clotet and J.A. Este. Anti-human immunodeficiency virus activity of novel aminoglycoside-arginine conjugates at early stages of infection. Aids Res. Human. Retrovir. 16, 627 (2000).[read online]
A. Lapidot and S. Haber, Effect of acute insulin-induced hyperglycemia on fetal vs. adult brain fuel utilization, assessed by 13 MRS isotopomer analysis of [U-13C]-glucose metabolites. Dev. Neurosci. 22, 444 (2000).[read online]
A. Litovchick, A.G. Evdokimov and A. Lapidot, Aminoglycoside-arginine conjugates that bind TAR RNA: synthesis, characterization and antiviral activity. Biochemistry 39, 2838 (2000).[read online]
G. Malin, R. Iakobashvili and A. Lapidot. Effect of tetrahydropyrimidine derivatives on protein-nucleic acids interaction. Type II restriction endonucleases as a model system. J. Biol. Chem. 274, 6920 (1999).[read online]
A. Litovchick, A.G.Evdokimov and A, Lapidot. Arginine-aminoglycoside conjugates that bind to HIV transactivation responsive element RNA in vitro. Febs Lett. 445, 73 (1999).[read online]
R. Iakobashevilli and A. Lapidot. Low temperature cycled PCR protocol for Klenow Fragment of DNA polymerase I in the presence of proline. Nucleic Acid Res. 27, 1566 (1999).[read online]
A. Lapidot and S. Litvin, Maternal diabetic effect on fetal cerebral glucose metabolism, 13C NMR isotopomer analysis. J. Neurochem. 69 (supplement) 280 (1997)
A. Lapidot and S. Litvin, Endogenous production of beta-HBA and uptake by young and fetal brains in diabetic young rabbit and during pregnancy, 13C NMR isotopomer analysis. J. Neurochem. 69 (supplement) 5273 (1997)
A. Lapidot and A. Gopher. Quantitation of metabolic compartmentation in hyperammonemic brain by natural abundance 13C NMR detection of 13C-15N coupling patterns and isotopic shifts. Eur. J. Biochem. 243, 597 (1997).
C. Barak, S. Litvin and A. Lapidot. The activity of pyruvate dehydrogenase vs. pyruvate carboxylase in fetal liver during maternal diabetes: 13C NMR isotopomer analysis. Magn. Res. Mat. Phys. Biol. and Med. Suppl. 105 (1996).
G. Malin and A. Lapidot, Synthesis of tetrahydropyrimidine derivatives in Streptomyces in response to osmotic and heat stress. J. Bacterial. 178, 385 (1996).
A. Lapidot Cerebral metabolic compartmentation as revealed by 13C NMR, 13C-13C and 13C.15N isotopomer analyses. Bull. Magn. Reson. 17, 264-265 (1996).
A Lapidot, E. Ben-Asher and M. Eisenstein, Tetrahydropyrimidine derivitives inhibit binding of a Tat-like, arginine-containing peptide to HIV RNA in vitro. FEBS Lett. 367, 33 (1995).
A. Lapidot and A. Gopher. Cerebral metabolic compartmentation. Estimation of glucose flux via pyruvate carboxylase/pyruvate dehydrogenase by 13C NMR isotopomer analysis D-[U-13C]glucose metabolites. J. Biol. Chem. 269, 27198 (1994).[read abstract]
A. Lapidot and A. Gopher. Cerebral metabolic compartmentation as revealed from [U-13C]glucose metabolisms by 13C NMR spin-spin couplings. Isotopically Labeled Compounds 587 (1994).
A. Lapidot and A. Gopher Cerebral metabolic compartmentation as revealed from [U-13C]glucose metabolism by 13C NMR spin-spin couplings. In Synthesis and Applications of Isotopically Labeled Compounds. 1994. Eds. J. Allen and R. Voges; Wiley, pp. 587-590 (1994).