The Experts below are selected from a list of 99 Experts worldwide ranked by ideXlab platform
Craig J Canfield - One of the best experts on this subject based on the ideXlab platform.
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clinical studies of atovaquone alone or in combination with other antimalarial drugs for treatment of acute uncomplicated malaria in thailand
American Journal of Tropical Medicine and Hygiene, 1996Co-Authors: Chaisin Viravan, Kyle H Webster, David B A Hutchinson, Dennis E Kyle, Craig J CanfieldAbstract:Abstract The therapy of Plasmodium falciparum malaria continues to be a problem in many parts of Southeast Asia because of multidrug resistance to nearly all existing antimalarial drugs. Atovaquone is a novel hydroxynaphthoquinone with broad spectrum anti-protozoal activity. We recently evaluated the antimalarial activity of atovaquone in a series of dose-ranging studies in 317 patients with malaria at the Bangkok Hospital for Tropical Diseases. Originally, the drug was administered alone. Using atovaquone alone resulted in satisfactory, initial clinical responses in all patients; the mean parasite and fever clearance times were 62 and 53 hr, respectively. However, irrespective of the duration of therapy, overall cure rates were approximately 67%. In vitro sensitivity studies on parasites taken from patients prior to treatment and at the time of recrudescence showed a marked decrease in susceptibility to atovaquone in the recrudescent parasites. To improve cure rates, atovaquone was administered in combination with other drugs with antimalarial activity. Proguanil and tetracycline were chosen due to laboratory evidence of potentiation; doxycycline was selected because it has a longer half-life than tetracycline. Although pyrimethamine did not show laboratory evidence of potentiation with atovaquone, it was chosen as an alternative inhibitor of Dihydrofolic Acid reductase with a longer half-life than proguanil. The clinical studies with these drug combinations confirmed the laboratory results with marked improvement in cure rates for proguanil, tetracycline, and doxycycline; pyrimethamine showed only minimal improvement. Proguanil was subsequently selected as the preferred drug partner because of its long record of safety and the ability to use the drug in pregnant women and children. Of the 104 patients with falciparum malaria treated with atovaquone plus proguanil for 3–7 days, 101 were cured and had virtually no adverse side effects. The combination of atovaquone and proguanil also was effective in eliminating erythrocytic forms of P. vivax, but parasitemia recurred in most patients.
Jeffrey Skolnick - One of the best experts on this subject based on the ideXlab platform.
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insights into the slow onset tight binding inhibition of escherichia coli dihydrofolate reductase detailed mechanistic characterization of pyrrolo 3 2 f quinazoline 1 3 diamine and its derivatives as novel tight binding inhibitors
FEBS Journal, 2015Co-Authors: Bharath Srinivasan, Jeffrey SkolnickAbstract:Dihydrofolate reductase, DHFR, is a pivotal enzyme involved in the de novo pathway for purine synthesis, and hence, represents an attractive target to disrupt systems that require rapid DNA turnover. The enzyme acquires resistance to available drugs by various molecular mechanisms, which necessitates the continuous discovery of novel antifolates. In a previous communication, we had identified a set of novel molecules that showed binding to E. coli DHFR by means of thermal shift without establishing whether they inhibited the enzyme. In this paper we show that a fraction of those molecules represent potent and novel inhibitors of DHFR activity. 7-[(4-aminophenyl)methyl]-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine, AMPQD, a molecule with no reported inhibition of DHFR, potently inhibits the enzyme with a Ki value of 7.42 ± 0.92 nM by competitive displacement of the substrate Dihydrofolic Acid. It shows uncompetitive inhibition vis-avis NADPH indicating that the inhibitor has markedly increased affinity for the NADPH-bound form of the enzyme. Further, we demonstrate that the mode of binding of the inhibitor to the enzyme-NADPH binary complex conforms to the slow-onset, tight-binding model. On the contrary, mechanistic characterization of the parent molecule 7H-pyrrolo[3,2-f] quinazoline-1,3-diamine, PQD, shows that the lack of (4-aminophenyl)-methyl group at the 7th position abolishes the slow-onset of inhibition. This finding provides novel insights on the role of substitutions on inhibitors of E. coli DHFR and represents the first detailed kinetic investigation of a novel diaminopyrroloquinazoline derivative on a prokaryotic DHFR. Furthermore, marked differences in the potency of inhibition for the E. coli and human DHFR makes this molecule a promising candidate for development as an antibiotic.
Aleem Gangjee - One of the best experts on this subject based on the ideXlab platform.
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trimethoprim resistance of dihydrofolate reductase variants from clinical isolates of pneumocystis jirovecii
Antimicrobial Agents and Chemotherapy, 2013Co-Authors: Sherry F. Queener, Vivian Cody, J Pace, P Torkelson, Aleem GangjeeAbstract:Pneumocystis jirovecii is an opportunistic pathogen that causes serious pneumonia in immunosuppressed patients. Standard therapy and prophylaxis include trimethoprim (TMP)-sulfamethoxazole; trimethoprim in this combination targets dihydrofolate reductase (DHFR). Fourteen clinically observed variants of P. jirovecii DHFR were produced recombinantly to allow exploration of the causes of clinically observed failure of therapy and prophylaxis that includes trimethoprim. Six DHFR variants (S31F, F36C, L65P, A67V, V79I, and I158V) showed resistance to inhibition by trimethoprim, with Ki values for trimethoprim 4-fold to 100-fold higher than those for the wild-type P. jirovecii DHFR. An experimental antifolate with more conformational flexibility than trimethoprim showed strong activity against one trimethoprim-resistant variant. The two variants that were most resistant to trimethoprim (F36C and L65P) also had increased Km values for Dihydrofolic Acid (DHFA). The catalytic rate constant (kcat) was unchanged for most variant forms of P. jirovecii DHFR but was significantly lowered in F36C protein; one naturally occurring variant with two amino Acid substitutions (S106P and E127G) showed a doubling of kcat, as well as a Km for NADPH half that of the wild type. The strongest resistance to trimethoprim occurred with amino Acid changes in the binding pocket for DHFA or trimethoprim, and the strongest effect on binding of NADPH was linked to a mutation involved in binding the phosphate group of the cofactor. This study marks the first confirmation that naturally occurring mutations in the gene for DHFR from P. jirovecii produce variant forms of DHFR that are resistant to trimethoprim and may contribute to clinically observed failures of standard therapy or prophylaxis.
Chaisin Viravan - One of the best experts on this subject based on the ideXlab platform.
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Canfiel CJ. Clinical studies of atovaquone, alone or in combinationwith other antimalarial drugs, for treatment of acute uncomplicated malaria
2016Co-Authors: Sornchai Looareesuwan, David B A Hutchinson, Kyle H Webster, Chaisin Viravan, E. Kyle, Andcraig J. CanfieldAbstract:Abstract. The therapy of Plasmodium falciparum malaria continues to be a problem in many parts of Southeast Asia because of multidrug resistance to nearly all existing antimalarial drugs. Atovaquone is a novel hydroxynaphth oquinone with broad spectrum anti-protozoal activity. We recently evaluated the antimalarial activity of atovaquone in a series of dose-ranging studies in 3 17 patients with malaria at the Bangkok Hospital for Tropical Diseases. Originally, the drug was administered alone. Using atovaquone alone resulted in satisfactory, initial clinical responses in all patients; the mean parasite and fever clearance times were 62 and 53 hr. respectively. However, irrespective of the duration of therapy, overall cure rates were approximately 67%. In vitro sensitivity studies on parasites taken from patients prior to treatment and at the time of recrudescence showed a marked decrease in susceptibility to atovaquonc in the recrudescent parasites. To improve cure rates, atovaquone was administered in combination with other drugs with antimalarial activity. Proguanil and tetracycline were chosen due to laboratory evidence of poten tiation; doxycycline was selected because it has a longer half-life than tetracycline. Although pyrimethaminc did not show laboratory evidence of potcntiation with atovaquone, it was chosen as an alternative inhibitor of Dihydrofolic Acid reductase with a longer half-life than proguanil. The clinical studies with these drug combinations confirmed the laboratory results with marked improvement in cure rates for proguanil, tetracycline, and doxycyclinc; pyrimethamin
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clinical studies of atovaquone alone or in combination with other antimalarial drugs for treatment of acute uncomplicated malaria in thailand
American Journal of Tropical Medicine and Hygiene, 1996Co-Authors: Chaisin Viravan, Kyle H Webster, David B A Hutchinson, Dennis E Kyle, Craig J CanfieldAbstract:Abstract The therapy of Plasmodium falciparum malaria continues to be a problem in many parts of Southeast Asia because of multidrug resistance to nearly all existing antimalarial drugs. Atovaquone is a novel hydroxynaphthoquinone with broad spectrum anti-protozoal activity. We recently evaluated the antimalarial activity of atovaquone in a series of dose-ranging studies in 317 patients with malaria at the Bangkok Hospital for Tropical Diseases. Originally, the drug was administered alone. Using atovaquone alone resulted in satisfactory, initial clinical responses in all patients; the mean parasite and fever clearance times were 62 and 53 hr, respectively. However, irrespective of the duration of therapy, overall cure rates were approximately 67%. In vitro sensitivity studies on parasites taken from patients prior to treatment and at the time of recrudescence showed a marked decrease in susceptibility to atovaquone in the recrudescent parasites. To improve cure rates, atovaquone was administered in combination with other drugs with antimalarial activity. Proguanil and tetracycline were chosen due to laboratory evidence of potentiation; doxycycline was selected because it has a longer half-life than tetracycline. Although pyrimethamine did not show laboratory evidence of potentiation with atovaquone, it was chosen as an alternative inhibitor of Dihydrofolic Acid reductase with a longer half-life than proguanil. The clinical studies with these drug combinations confirmed the laboratory results with marked improvement in cure rates for proguanil, tetracycline, and doxycycline; pyrimethamine showed only minimal improvement. Proguanil was subsequently selected as the preferred drug partner because of its long record of safety and the ability to use the drug in pregnant women and children. Of the 104 patients with falciparum malaria treated with atovaquone plus proguanil for 3–7 days, 101 were cured and had virtually no adverse side effects. The combination of atovaquone and proguanil also was effective in eliminating erythrocytic forms of P. vivax, but parasitemia recurred in most patients.
Vivian Cody - One of the best experts on this subject based on the ideXlab platform.
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trimethoprim resistance of dihydrofolate reductase variants from clinical isolates of pneumocystis jirovecii
Antimicrobial Agents and Chemotherapy, 2013Co-Authors: Sherry F. Queener, Vivian Cody, J Pace, P Torkelson, Aleem GangjeeAbstract:Pneumocystis jirovecii is an opportunistic pathogen that causes serious pneumonia in immunosuppressed patients. Standard therapy and prophylaxis include trimethoprim (TMP)-sulfamethoxazole; trimethoprim in this combination targets dihydrofolate reductase (DHFR). Fourteen clinically observed variants of P. jirovecii DHFR were produced recombinantly to allow exploration of the causes of clinically observed failure of therapy and prophylaxis that includes trimethoprim. Six DHFR variants (S31F, F36C, L65P, A67V, V79I, and I158V) showed resistance to inhibition by trimethoprim, with Ki values for trimethoprim 4-fold to 100-fold higher than those for the wild-type P. jirovecii DHFR. An experimental antifolate with more conformational flexibility than trimethoprim showed strong activity against one trimethoprim-resistant variant. The two variants that were most resistant to trimethoprim (F36C and L65P) also had increased Km values for Dihydrofolic Acid (DHFA). The catalytic rate constant (kcat) was unchanged for most variant forms of P. jirovecii DHFR but was significantly lowered in F36C protein; one naturally occurring variant with two amino Acid substitutions (S106P and E127G) showed a doubling of kcat, as well as a Km for NADPH half that of the wild type. The strongest resistance to trimethoprim occurred with amino Acid changes in the binding pocket for DHFA or trimethoprim, and the strongest effect on binding of NADPH was linked to a mutation involved in binding the phosphate group of the cofactor. This study marks the first confirmation that naturally occurring mutations in the gene for DHFR from P. jirovecii produce variant forms of DHFR that are resistant to trimethoprim and may contribute to clinically observed failures of standard therapy or prophylaxis.