The Experts below are selected from a list of 174 Experts worldwide ranked by ideXlab platform
Lizbeth Hedstrom - One of the best experts on this subject based on the ideXlab platform.
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Phthalazinone inhibitors of inosine-5'-monophosphate dehydrogenase from Cryptosporidium parvum.
Bioorganic & medicinal chemistry letters, 2012Co-Authors: Corey R. Johnson, Minjia Zhang, Gregory D. Cuny, Suresh Kumar Gorla, Mandapati Kavitha, Xiaoping Liu, Boris Striepen, Jan R. Mead, Lizbeth HedstromAbstract:Abstract Cryptosporidium parvum (Cp) is a potential biowarfare agent and major cause of diarrhea and malnutrition. This protozoan parasite relies on inosine 5′-monophosphate dehydrogenase (IMPDH) for the production of guanine nucleotides. A CpIMPDH-selective N-aryl-3,4-dihydro-3-methyl-4-oxo-1-phthalazineacetamide inhibitor was previously identified in a high throughput screening campaign. Herein we report a structure–activity relationship study for the phthalazinone-based series that resulted in the discovery of benzofuranamide analogs that exhibit low nanomolar inhibition of CpIMPDH. In addition, the antiparasitic activity of select analogs in a Toxoplasma gondii model of C. parvum infection is also presented.
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Triazole inhibitors of Cryptosporidium parvum inosine 5′-monophosphate dehydrogenase
Journal of medicinal chemistry, 2009Co-Authors: Sushil K. Maurya, Deviprasad R. Gollapalli, Shivapriya Kirubakaran, Minjia Zhang, Corey R. Johnson, Nicole N. Benjamin, Lizbeth Hedstrom, Gregory D. CunyAbstract:Cryptosporidium parvum is an important human pathogen and potential bioterrorism agent. This protozoan parasite cannot salvage guanine or guanosine and therefore relies on inosine 5'-monophosphate dehydrogenase (IMPDH) for biosynthesis of guanine nucleotides and hence for survival. Because C. parvum IMPDH is highly divergent from the host counterpart, selective inhibitors could potentially be used to treat cryptosporidiosis with minimal effects on its mammalian host. A series of 1,2,3-triazole containing ether CpIMPDH inhibitors are described. A structure-activity relationship study revealed that a small alkyl group on the alpha-position of the ether was required, with the (R)-enantiomer significantly more active than the (S)-enantiomer. Electron-withdrawing groups in the 3- and/or 4-positions of the pendent phenyl ring were best, and conversion of the quinoline containing inhibitors to quinoline-N-oxides retained inhibitory activity both in the presence and absence of bovine serum albumin. The 1,2,3-triazole CpIMPDH inhibitors provide new tools for elucidating the role of IMPDH in C. parvum and may serve as potential therapeutics for treating cryptosporidiosis.
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Crystal structure at 2.4 A resolution of Borrelia burgdorferi inosine 5'-monophosphate dehydrogenase: evidence of a substrate-induced hinged-lid motion by loop 6.
Biochemistry, 2000Co-Authors: Fiona M. Mcmillan, Lizbeth Hedstrom, Marguerite Cahoon, Andre White, Gregory A. Petsko, Dagmar RingeAbstract:The conversion of inosine 5‘-monophosphate (IMP) to xanthosine 5‘-monophosphate (XMP) is the committed and rate-limiting reaction in de novo guanine nucleotide biosynthesis. Inosine 5‘- monophosphate dehydrogenase (IMPDH) is the enzyme that catalyzes the oxidation of IMP to XMP with the concomitant reduction of nicotinamide adenine dinucleotide (from NAD+ to NADH). Because of its critical role in purine biosynthesis, IMPDH is a drug design target for anticancer, antiinfective, and immunosuppressive chemotherapy. We have determined the crystal structure of IMPDH from Borrelia burgdorferi, the bacterial spirochete that causes Lyme disease, with a sulfate ion bound in the IMP phosphate binding site. This is the first structure of IMPDH in the absence of substrate or cofactor where the active-site loop (loop 6), which contains the essential catalytic residue Cys 229, is clearly defined in the electron density. We report that a seven residue region of loop 6, including Cys229, is tilted more than 6 A away from...
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Monovalent cation activation in Escherichia coli inosine 5'-monophosphate dehydrogenase.
Archives of biochemistry and biophysics, 2000Co-Authors: Kathleen M. Kerr, Marguerite Cahoon, Daryl A. Bosco, Lizbeth HedstromAbstract:Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes the oxidation of inosine 5'-monophosphate (IMP) to xanthosine 5'-monophosphate with the concomitant reduction of NAD to NADH. Escherichia coli IMPDH is activated by K(+), Rb(+), NH(+)(4), and Cs(+). K(+) activation is inhibited by Li(+), Na(+), Ca(2+), and Mg(2+). This inhibition is competitive versus K(+) at high K(+) concentrations, noncompetitive versus IMP, and competitive versus NAD. Thus monovalent cation activation is linked to the NAD site. K(+) increases the rate constant for the pre-steady-state burst of NADH production, possibly by increasing the affinity of NAD. Three mutant IMPDHs have been identified which increase the value of K(m) for K(+): Asp13Ala, Asp50Ala, and Glu469Ala. In contrast to wild type, both Asp13Ala and Glu469Ala are activated by all cations tested. Thus these mutations eliminate cation selectivity. Both Asp13 and Glu469 appear to interact with the K(+) binding site identified in Chinese hamster IMPDH. Like wild-type IMPDH, K(+) activation of Asp50Ala is inhibited by Li(+), Na(+), Ca(2+), and Mg(2+). However, this inhibition is noncompetitive with respect to K(+) and competitive with respect to both IMP and NAD. Asp50 interacts with residues that form a rigid wall in the IMP site; disruption of this wall would be expected to decrease IMP binding, and the defect could propagate to the proposed K(+) site. Alternatively, this mutation could uncover a second monovalent cation binding site.
Gregory D. Cuny - One of the best experts on this subject based on the ideXlab platform.
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Phthalazinone inhibitors of inosine-5'-monophosphate dehydrogenase from Cryptosporidium parvum.
Bioorganic & medicinal chemistry letters, 2012Co-Authors: Corey R. Johnson, Minjia Zhang, Gregory D. Cuny, Suresh Kumar Gorla, Mandapati Kavitha, Xiaoping Liu, Boris Striepen, Jan R. Mead, Lizbeth HedstromAbstract:Abstract Cryptosporidium parvum (Cp) is a potential biowarfare agent and major cause of diarrhea and malnutrition. This protozoan parasite relies on inosine 5′-monophosphate dehydrogenase (IMPDH) for the production of guanine nucleotides. A CpIMPDH-selective N-aryl-3,4-dihydro-3-methyl-4-oxo-1-phthalazineacetamide inhibitor was previously identified in a high throughput screening campaign. Herein we report a structure–activity relationship study for the phthalazinone-based series that resulted in the discovery of benzofuranamide analogs that exhibit low nanomolar inhibition of CpIMPDH. In addition, the antiparasitic activity of select analogs in a Toxoplasma gondii model of C. parvum infection is also presented.
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Triazole inhibitors of Cryptosporidium parvum inosine 5′-monophosphate dehydrogenase
Journal of medicinal chemistry, 2009Co-Authors: Sushil K. Maurya, Deviprasad R. Gollapalli, Shivapriya Kirubakaran, Minjia Zhang, Corey R. Johnson, Nicole N. Benjamin, Lizbeth Hedstrom, Gregory D. CunyAbstract:Cryptosporidium parvum is an important human pathogen and potential bioterrorism agent. This protozoan parasite cannot salvage guanine or guanosine and therefore relies on inosine 5'-monophosphate dehydrogenase (IMPDH) for biosynthesis of guanine nucleotides and hence for survival. Because C. parvum IMPDH is highly divergent from the host counterpart, selective inhibitors could potentially be used to treat cryptosporidiosis with minimal effects on its mammalian host. A series of 1,2,3-triazole containing ether CpIMPDH inhibitors are described. A structure-activity relationship study revealed that a small alkyl group on the alpha-position of the ether was required, with the (R)-enantiomer significantly more active than the (S)-enantiomer. Electron-withdrawing groups in the 3- and/or 4-positions of the pendent phenyl ring were best, and conversion of the quinoline containing inhibitors to quinoline-N-oxides retained inhibitory activity both in the presence and absence of bovine serum albumin. The 1,2,3-triazole CpIMPDH inhibitors provide new tools for elucidating the role of IMPDH in C. parvum and may serve as potential therapeutics for treating cryptosporidiosis.
Mathias M Mueller - One of the best experts on this subject based on the ideXlab platform.
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effect of mycophenolate mofetil therapy on inosine monophosphate dehydrogenase induction in red blood cells of heart transplant recipients
Clinical Pharmacology & Therapeutics, 2001Co-Authors: Guenter Weigel, A Zuckermann, Guenther Laufer, Andrea Griesmacher, Mathias M MuellerAbstract:Background Mycophenolic acid is reported to provide effective immunosuppression by inhibiting inosine monophosphate dehydrogenase. In an attempt to monitor the biological effects of long-term therapy with mycophenolate mofetil, we measured levels of guanosine 5′ triphosphate and adenosine 5′ triphosphate in red blood cells (RBCs) of patients after heart transplantations. Methods Fifty-two patients enrolled in the study were randomly assigned to one of two groups. Patients in the control group (n = 27) received cyclosporine A (INN, ciclosporin), azathioprine, and prednisone. Patients in the study group (n = 25) were switched from azathioprine to mycophenolate mofetil 3 months after the heart transplantation. Adenosine 5′ triphosphate and guanosine 5′ triphosphate levels were determined by means of HPLC. The activities of inosine monophosphate dehydrogenase and hypoxanthine-guanine phosphoribosyltransferase, which are responsible for guanine nucleotide formation, were measured in RBCs by radiochemical methods. Results Adenosine 5′ triphosphate levels were unchanged in patients treated with mycophenolate mofetil, whereas those of the control group who received azathioprine (from 142 ± 26 pmol/106 RBCs to 165 ± 25 pmol/106 RBCs; P < .001) increased. As the length of mycophenolate mofetil therapy increased, patients in the study group showed significantly elevated guanosine 5′ triphosphate levels (15.6 ± 6.1 pmol/106 RBCs versus 6.6 ± 2.1 pmol/106 RBCs; P < .001) and a 5-fold increase in inosine monophosphate dehydrogenase activity (108.6 ± 13.3 pmol/mg of protein per hour versus 22.5 ± 1.7 pmol/mg of protein per hour; P < .001) compared with the control group. In addition, a slight but significant enhancement of hypoxanthine-guanine phosphoribosyltransferase activity was seen in the mycophenolate mofetil group. Conclusions Our studies have shown that long-term administration of mycophenolate mofetil is associated with increasing guanosine 5′ triphosphate levels in RBCs as the result of an induction of inosine monophosphate dehydrogenase and hypoxanthine-guanine phosphoribosyltransferase activities in erythrocytes. Clinical Pharmacology & Therapeutics (2001) 69, 137–144; doi: 10.1067/mcp.2001.114166
Corey R. Johnson - One of the best experts on this subject based on the ideXlab platform.
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Phthalazinone inhibitors of inosine-5'-monophosphate dehydrogenase from Cryptosporidium parvum.
Bioorganic & medicinal chemistry letters, 2012Co-Authors: Corey R. Johnson, Minjia Zhang, Gregory D. Cuny, Suresh Kumar Gorla, Mandapati Kavitha, Xiaoping Liu, Boris Striepen, Jan R. Mead, Lizbeth HedstromAbstract:Abstract Cryptosporidium parvum (Cp) is a potential biowarfare agent and major cause of diarrhea and malnutrition. This protozoan parasite relies on inosine 5′-monophosphate dehydrogenase (IMPDH) for the production of guanine nucleotides. A CpIMPDH-selective N-aryl-3,4-dihydro-3-methyl-4-oxo-1-phthalazineacetamide inhibitor was previously identified in a high throughput screening campaign. Herein we report a structure–activity relationship study for the phthalazinone-based series that resulted in the discovery of benzofuranamide analogs that exhibit low nanomolar inhibition of CpIMPDH. In addition, the antiparasitic activity of select analogs in a Toxoplasma gondii model of C. parvum infection is also presented.
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Triazole inhibitors of Cryptosporidium parvum inosine 5′-monophosphate dehydrogenase
Journal of medicinal chemistry, 2009Co-Authors: Sushil K. Maurya, Deviprasad R. Gollapalli, Shivapriya Kirubakaran, Minjia Zhang, Corey R. Johnson, Nicole N. Benjamin, Lizbeth Hedstrom, Gregory D. CunyAbstract:Cryptosporidium parvum is an important human pathogen and potential bioterrorism agent. This protozoan parasite cannot salvage guanine or guanosine and therefore relies on inosine 5'-monophosphate dehydrogenase (IMPDH) for biosynthesis of guanine nucleotides and hence for survival. Because C. parvum IMPDH is highly divergent from the host counterpart, selective inhibitors could potentially be used to treat cryptosporidiosis with minimal effects on its mammalian host. A series of 1,2,3-triazole containing ether CpIMPDH inhibitors are described. A structure-activity relationship study revealed that a small alkyl group on the alpha-position of the ether was required, with the (R)-enantiomer significantly more active than the (S)-enantiomer. Electron-withdrawing groups in the 3- and/or 4-positions of the pendent phenyl ring were best, and conversion of the quinoline containing inhibitors to quinoline-N-oxides retained inhibitory activity both in the presence and absence of bovine serum albumin. The 1,2,3-triazole CpIMPDH inhibitors provide new tools for elucidating the role of IMPDH in C. parvum and may serve as potential therapeutics for treating cryptosporidiosis.
Anne-françoise Pétavy - One of the best experts on this subject based on the ideXlab platform.
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Effects of purine nucleosides on the in vitro growth of Cryptosporidium parvum
FEMS Microbiology Letters, 2003Co-Authors: Philippe Lawton, Carine Hejl, Roselyne Mancassola, Muriel Naciri, Anne-françoise PétavyAbstract:The effect of purine nucleosides on the in vitro growth of Cryptosporidium parvum was studied. Culturing the parasite in THP-1 cells for 72 h in growth medium supplemented with adenosine or inosine improved the parasite yields especially in the first 48 h. Similar results were obtained with parasites cultured in Madin^Darby bovine kidney cells and incubated for 24 h with inosine. The addition of inosine to 72-h cultures enhanced the growth of C. parvum in THP-1 cells, especially the trophic stages, whereas the analogue formycin B was toxic to the parasites and induced a marked decrease in the gamont stages. The monitoring of the added purine nucleosides by high performance liquid chromatography showed that at 37 ‡C in the presence of THP-1 cells, a rapid uptake of inosine occurred with hypoxanthine being the main purine present after 2 h in the medium.