Alexander Kots, Ph.D.
Instructor, Center for Cell Signaling
phone 713.500.2482;
fax 713.500.2424
Alexander.Y.Kots@uth.tmc.edu
The main research interests of Dr. Kots lie in the development of new agents capable
of
inhibiting or activating synthesis of cyclic nucleotides in animal cells
Dr. Alexander Kots received his MS degree in 1988 and his Ph.D. degree in 1992 from the Department of Biochemistry, Lomonosov Moscow State University, Moscow, Russia. He did his postdoctoral training in the Department of Physiology and Biophysics at the University of Southern California Medical School, Los Angeles and returned to Russia for six years as a Scientist in the Department of Bioorganic Chemistry, Moscow State University. He was recruited to Nobel Laureate Dr. Ferid Murad's laboratory and appointed Instructor in the Department of Integrative Biology and Pharmacology at the University of Texas Medical School at Houston in 2001. In 2005 he was also appointed as Instructor in the Center for Cell Signaling at the Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, the University of Texas Health Science Center at Houston.
The professional experience of Dr. Kots lies in the fields of biochemistry, pharmacology, medicinal and combinatorial chemistry, high through output screening, and drug development with a major focus on the regulatory properties of enzymes which synthesize cyclic nucleotides, small second messenger molecules tightly linked to every aspect of cellular physiology. Studies of adenylyl cyclase included GTP-binding proteins and ADP-ribosylation reactions catalyzed by bacterial toxins (cholera, diphtheria, and pertussis toxins) and endogenous ADP-ribosyltransferases. Soluble guanylyl cyclase activation by nitric oxide and allosteric regulators and inhibition of the enzyme by natural and synthetic compounds and by interaction with various cellular proteins was extensively studied. As a result of these studies, a number of activators and inhibitors of cyclic GMP synthesis were developed and tested in various physiological models.
His main research project is presently directed towards development of novel inhibitors of membrane-bound guanylyl cyclase, specifically intestinal guanylyl cyclase type C (GC-C). By screening of a chemical compound library, a potent lead compound has been recently identified. Preliminary data suggest that this lead compound can be used for therapy of various diarrheal diseases and other pathologies associated with abnormal functioning of cyclic nucleotide synthesis including therapy of infections with anthrax, whooping cough, and cholera as well as certain types of tumors and cardiovascular disorders. Other minor research projects involve studies of novel nitric oxide donors and guanylyl cyclase activators on penile erection to evaluate possible relevance for therapy of impotence, mechanisms of regulation of expression and activity of soluble guanylyl cyclase in stem cells and neuronal cells; effects of heat shock proteins on guanylyl cyclase activity, and development of new heme-dependent inhibitors of soluble guanylyl cyclase which are active in an animal model in vivo.
All these exciting projects are carried out in cooperation with a number of very prominent scientists in the United States (University of Virginia, University of Texas Medical Branch in Galveston, Baylor College of Medicine, University of Texas at Austin, etc.) and in other countries (Russia, England, Turkey, Italy, Finland).
Dr. Kots is a member of the American Chemical Society and is a reviewer in a number of Russian biological journals. He is a recipient of the George Soros International Science Foundation Award and Moscow State University Young Investigator Award. He is also serving a third term on the UT-Houston Medical School Faculty Senate.
Selected most cited publications:
Kots, A.Y., Grafov, M.A., Khropov, Y.V., Betin, V.L., Belushkina, N.N., Busygina, O.G., Yazykova, M.Y., Ovchinnikov, I.V., Kulikov, A.S., Makhova, N.N., Medvedeva, N.A., Bulargina, T.V., and Severina, I.S.: Vasorelaxant and antiplatelet activity of 4,7-dimethyl-1,2, 5-oxadiazolo[3,4-d]pyridazine 1,5,6-trioxide: role of soluble guanylate cyclase, nitric oxide and thiols. Br. J. Pharmacol., 129:1163-1177, 2000.
Wang, J., Nemoto, E., Kots, A.Y., Kaslow, H.R., and Dennert, G.: Regulation of cytotoxic T cells by ecto-NAD correlates with a cell surface GPI-anchored NAD:arginine ADP-ribosyltransferase. J. Immunol., 153:4048-4058, 1994.
Kots, A.Y., Gumanova, N.G., Akhmedzhanov, N.M., Varentsov, S.I., Gerasimova, C.I., Bulargina, T.V., and Shakhov, Yu.A.: The GTP-binding regulatory proteins, Gs and Gi, are altered in erythrocyte membranes of patients with ischemic heart disease resulting from coronary atherosclerosis. Arterioscler. Thromb., 13:1244-1251, 1993.
Kots, A.Y., Sergienko, E.A., Bulargina, T.V., and Severin, E.S. Glyceraldehyde-3-phosphate activates auto-ADP-ribosylation of glyceraldehyde-3-phosphate dehydrogenase. FEBS Lett., 324:33-36, 1993.
Kots, A.Y., Skurat, A.V., Sergienko, E.A., Bulargina, T.V., and Severin, E.S.: Nitroprusside stimulates the cysteine-specific mono(ADP-ribosylation) of glyceraldehyde-3-phosphate dehydrogenase from human erythrocytes. FEBS Lett., 300:9-12, 1992.
Selected patents:
Kots AY, Kulikov A.S., Khropov YV, Ovchinnikov IV, Belushkina NN, Busygina OG, Shmalhausen EV, Yazykova MY, Mast NV, Yakimova, NG, Lopina OD, Makhova NN, Bulargina TV, Muronetz VI, Severina IS (1997) A specific regulator of activity of nucleotide-dependent enzymes. Patent RU 2130490. "4,7-dimethyl-1,2,5-oxadiazolo[3,4-d]pyridazine-5,6-dioxide and 4,7-dimethyl-1,2,5-oxadiazolo[3,4-d]pyridazine-1,5,6-trioxide as specific regulators of activity of nucleotide-dependent enzymes (guanylate cyclase, glyceraldehyde-3-phosphate dehydrogenase, alcohol dehydrogenase, and H+,K+-ATPase)".
Kots AY, Khropov YV, Grafov MA, Kulikov AS, Ovchinnikov IV, Belushkina NN, Busygina OG, Gavrilova SA, Makhova NN, Medvedeva NA, Bulargina TV, Severina IS (1997) Derivatives of 1,2,5-oxadiazole [3,4-d]pyridazine 5,6-dioxide as activators of soluble guanylate cyclase and medication for treatment of cardiovascular disorders and pharmaceutical compositions of these derivatives. Patent RU 2165256.
Kots AY, Batog LV, Betin VL, Rozhkov VY, Ukraintsev KE, Khropov YV, Epishina MA, Sheremetev AB, Makhova NN, Bulargina TV (1999) Inhibition of guanylate cyclase soluble isoform by azo-bis-(1,2,6-oxadiazole) derivatives.. Patent RU 2151799.
Khropov YV, Kots AY, Postnikov AB, Bogdanova NG, Gavrilova SA, Grafov MA, Volchkova IL., Pyatakova NV, Betin VL, Kulikov AS, Ovchinnikov IV, Zapesochnaya GG, Matveenko VN, Makhova NN, Medvedeva NA, Severina IS, Bulargina TV (1999) Inclusion complexes of derivatives of 1,2,5-oxadiazol-2-oxide with polycyclic derivatives of glucopyranose, their preparation, and a pharmaceutical composition. Patent RU 2186782.
Sheremetev AB, Betin VL, Yudin IL, Kulagina VO, Khropov YV, Bulargina TV, Kots AY (2000) Derivatives of tetrafurazano[3,4-b:3’4’-f:3’’,4’’-j:3’’’,4’’’-N][1,4,5,8,9,12,13,16]octaazabicyclo[14.2.2]eikosa-4,8,12-triene and method of their synthesis. Patent RU 2167161.
Pirogov SV, Kots AY, Mel’nikova SF, Postnikov AB, Betin VL, Shmal’hausen E.V., Khropov YuV, Muronetz VI, Tselinsky IV, Bulargina TV. A preparation of 1,4,2,5-dioxadiazine derivatives useful as selective activators of soluble form of guanylate cyclase. Patent RU 2212409.
Kots AY, Pirogov SV, Melnikova SF, Tselinsky IV, Romanova TV, Spiridonova NP, Betin VL, Postnikov AB, Khropov YV, Gavrilova SA, Grafov MA, Medvedeva NA, Pyatakova NV, Severina IS, Bulargina TV. (2004) A preparation of 3,4-bis(furazan-3-yl)furoxan derivatives as selective NO-donors, useful for activation of guanylate cyclase soluble form, inhibition of platelet aggregation, and eliciting spasmolytic, vasodilating, hypotensive effect.. Patent RU 2240321.
Recently submitted provisional US patent application:
13. Murad F, Kots AY, Choi B-K. (2006) Inhibitors of cyclic nucleotide synthesis and their use for therapy of various diseases. Patent US60/806,942 (provisional).
Recent publications:
Gocmen C, Buyuknacar HS, Kots AY, Murad F, Kiroglu O, Kumcu EK. (2005) The relaxant activity of 4,7-dimethyl-1,2,5-oxadiazolo[3,4-d]pyridazine 1,5,6-trioxide in the mouse corpus cavernosum. J Pharmacol Exp Ther., in Press.
Krumenacker JS, Katsuki S, Kots A, Murad F. (2005) Differential expression of genes involved in cGMP-dependent nitric oxide signaling in murine embryonic stem (ES) cells and ES cell-derived cardiomyocytes. Nitric Oxide, in Press.
Krumenacker JS, Kots A, Murad F. (2005) Effects of the JNK inhibitor anthra[1,9-cd]pyrazol-6(2H)-one (SP-600125) on soluble guanylyl cyclase alpha1 gene regulation and cGMP synthesis. Am J Physiol Cell Physiol., 289:C778-784.