Biomedical subjects

A M Aronov

Publications and source records attributed to A M Aronov.

8 recordsLinked to original sources

PubMed2001

Adenosine analogues as selective inhibitors of glyceraldehyde-3-phosphate dehydrogenase of Trypanosomatidae via structure-based drug design.

In our continuation of the structure-based design of anti-trypanosomatid drugs, parasite-selective adenosine analogues were identified as low micromolar inhibitors of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Crystal structures of Trypanosoma brucei, Trypanosoma cruzi, Leishmania mexicana, and human GAPDH's provided details of how the adenosyl moiety of NAD(+) interacts with the proteins, and this facilitated the understanding of the relative affinities of a series of adenosine analogues for the various GAPDH's. From exploration of modifications of the naphthalenemethyl and benzamide substituents of a lead compound, N(6)-(1-naphthalenemethyl)-2'-deoxy-2'-(3-methoxybenzamido)adenosine (6e), N(6)-(substituted-naphthalenemethyl)-2'-deoxy-2'-(substituted-benzamido)adenosine analogues were investigated. N(6)-(1-Naphthalenemethyl)-2'-deoxy-2'-(3,5-dimethoxybenzamido)adenosine (6m), N(6)-[1-(3-hydroxynaphthalene)methyl]-2'-deoxy-2'-(3,5-dimethoxybenzamido)adenosine (7m), N(6)-[1-(3-methoxynaphthalene)methyl]-2'-deoxy-2'-(3,5-dimethoxybenzamido)adenosine (9m), N(6)-(2-naphthalenemethyl)-2'-deoxy-2'-(3-methoxybenzamido)adenosine (11e), and N(6)-(2-naphthalenemethyl)-2'-deoxy-2'-(3,5-dimethoxybenzamido)adenosine (11m) demonstrated a 2- to 3-fold improvement over 6e and a 7100- to 25000-fold improvement over the adenosine template. IC(50)'s of these compounds were in the range 2-12 microM for T. brucei, T. cruzi, and L. mexicana GAPDH's, and these compounds did not inhibit mammalian GAPDH when tested at their solubility limit. To explore more thoroughly the structure-activity relationships of this class of compounds, a library of 240 N(6)-(substituted)-2'-deoxy-2'-(amido)adenosine analogues was generated using parallel solution-phase synthesis with N(6) and C2' substituents chosen on the basis of computational docking scores. This resulted in the identification of 40 additional compounds that inhibit parasite GAPDH's in the low micromolar range. We also explored adenosine analogues containing 5'-amido substituents and found that 2',5'-dideoxy-2'-(3,5-dimethoxybenzamido)-5'-(diphenylacetamido)adenosine (49) displays an IC(50) of 60-100 microM against the three parasite GAPDH's.

3T3 Cells↗

PubMed2001

Virtual screening of combinatorial libraries across a gene family: in search of inhibitors of Giardia lamblia guanine phosphoribosyltransferase.

Parasitic protozoa lack the ability to synthesize purine nucleotides de novo, relying instead on purine salvage enzymes for their survival. Guanine phosphoribosyltransferase (GPRT) from the protozoan parasite Giardia lamblia is a potential target for rational antiparasitic drug design, based on the experimental evidence, which indicates the lack of interconversion between adenine and guanine nucleotide pools. The present study is a continuation of our efforts to use three-dimensional structures of parasitic phosphoribosyltransferases (PRTs) to design novel antiparasitic agents. Two micromolar phthalimide-based GPRT inhibitors were identified by screening the in-house phthalimide library. A combination of structure-based scaffold selection using virtual library screening across the PRT gene family and solid phase library synthesis led to identification of smaller (molecular weight, <300) ligands with moderate to low specificity for GPRT; the best inhibitors, GP3 and GP5, had K(i) values in the 23 to 25 microM range. These results represent significant progress toward the goal of designing potent inhibitors of purine salvage in Giardia parasites. As a second step in this process, altering the phthalimide moiety to optimize interactions in the guanine-binding pocket of GPRT is expected to lead to compounds with promising activity against G. lamblia PRT.

Animals↗

PubMed2000

Rational design of selective submicromolar inhibitors of Tritrichomonas foetus hypoxanthine-guanine-xanthine phosphoribosyltransferase.

All parasitic protozoa lack the ability to synthesize purine nucleotides de novo, relying instead on purine salvage enzymes for their survival. Hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) from the protozoan parasite Tritrichomonas foetus is a rational target for antiparasitic drug design because it is the primary enzyme the parasite uses to salvage purine bases from the host. The study presented here is a continuation of our efforts to use the X-ray structure of the T. foetus HGXPRT-GMP complex to design compounds that bind tightly to the purine pocket of HGXPRT. The goal of the current project was to improve the affinity and selectivity of previously identified HGXPRT inhibitor TF1 [4-(3-nitroanilino)phthalic anhydride]. A virtual library of substituted 4-phthalimidocarboxanilides was constructed using methods of structure-based drug design, and was implemented synthetically on solid support. Compound 20 [(4'-phthalimido)carboxamido-3-benzyloxybenzene] was then used as a secondary lead for the second round of combinatorial chemistry, producing a number of low-micromolar inhibitors of HGXPRT. One of these compounds, TF2 [(4'-phthalimido)carboxamido-3-(4-bromobenzyloxy)benzene], was further characterized as a competitive inhibitor of T. foetus HGXPRT with respect to guanine with a K(I) of 0.49 microM and a 30-fold selectivity over the human HGPRT. TF2 inhibited the growth of cultured T. foetus cells in a concentration-dependent manner with an ED(50) of 2.8 microM, and this inhibitory effect could be reversed by addition of exogenous hypoxanthine. These studies underscore the efficiency of combining structure-based drug design with combinatorial chemistry to produce effective species-specific enzyme inhibitors of medicinal importance.

Anilides↗

PubMed1999

Structure-based design of submicromolar, biologically active inhibitors of trypanosomatid glyceraldehyde-3-phosphate dehydrogenase.

The bloodstream stage of Trypanosoma brucei and probably the intracellular (amastigote) stage of Trypanosoma cruzi derive all of their energy from glycolysis. Inhibiting glycolytic enzymes may be a novel approach for the development of antitrypanosomatid drugs provided that sufficient parasite versus host selectivity can be obtained. Guided by the crystal structures of human, T. brucei, and Leishmania mexicana glyceraldehyde-3-phosphate dehydrogenase, we designed adenosine analogs as tight binding inhibitors that occupy the pocket on the enzyme that accommodates the adenosyl moiety of the NAD+ cosubstrate. Although adenosine is a very poor inhibitor, IC50 approximately 50 mM, addition of substituents to the 2' position of ribose and the N6-position of adenosine led to disubstituted nucleosides with micromolar to submicromolar potency in glyceraldehyde-3-phosphate dehydrogenase assays, an improvement of 5 orders of magnitude over the lead. The designed compounds do not inhibit the human glycolytic enzyme when tested up to their solubility limit (approximately 40 microM). When tested against cultured bloodstream T. brucei and intracellular T. cruzi, N6-(1-naphthalenemethyl)-2'-(3-chlorobenzamido)adenosine inhibited growth in the low micromolar range. Within minutes after adding this compound to bloodstream T. brucei, production of glucose-derived pyruvate ceased, parasite motility was lost, and a mixture of grossly deformed and lysed parasites was observed. These studies underscore the feasibility of using structure-based drug design to transform a mediocre lead compound into a potent enzyme inhibitor. They also suggest that energy production can be blocked in trypanosomatids with a tight binding competitive inhibitor of an enzyme in the glycolytic pathway.

3T3 Cells↗

PubMed1998

Synthesis and structure-activity relationships of adenosine analogs as inhibitors of trypanosomal glyceraldehyde-3-phosphate dehydrogenase. Modifications at positions 5' and 8.

A number of 5', N6- and C8, N6-disubstituted adenosine analogs was synthesized and tested for inhibition of trypanosomal glyceraldehyde 3-phosphate dehydrogenase. The most active compound, N6-(3-methyl-2-butenyl)-8-(2-thienyl)adenosine, had Kl of 9 microM and was marginally selective for the parasite enzyme.

Adenosine↗

PubMed1998

Selective tight binding inhibitors of trypanosomal glyceraldehyde-3-phosphate dehydrogenase via structure-based drug design.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from the sleeping sickness parasite Trypanosoma brucei is a rational target for anti-trypanosomatid drug design because glycolysis provides virtually all of the energy for the bloodstream form of this parasite. Glycolysis is also an important source of energy for other pathogenic parasites including Trypanosoma cruzi and Leishmania mexicana. The current study is a continuation of our efforts to use the X-ray structures of T. brucei and L. mexicana GAPDHs containing bound NAD+ to design adenosine analogues that bind tightly to the enzyme pocket that accommodates the adenosyl moiety of NAD+. The goal was to improve the affinity, selectivity, and solubility of previously reported 2'-deoxy-2'-(3-methoxybenzamido)adenosine (1). It was found that introduction of hydroxyl functions on the benzamido ring increases solubility without significantly affecting enzyme inhibition. Modifications at the previously unexploited N6-position of the purine not only lead to a substantial increase in inhibitor potency but are also compatible with the 2'-benzamido moiety of the sugar. For N6-substituted adenosines, two successive rounds of modeling and screening provided a 330-fold gain in affinity versus that of adenosine. The combination of N6- and 2'-substitutions produced significantly improved inhibitors. N6-Benzyl (9a) and N6-2-methylbenzyl (9b) derivatives of 1 display IC50 values against L. mexicana GAPDH of 16 and 4 microM, respectively (3100- and 12500-fold more potent than adenosine). The adenosine analogues did not inhibit human GAPDH. These studies underscore the usefulness of structure-based drug design for generating potent and species-selective enzyme inhibitors of medicinal importance starting from a weakly binding lead compound.

Adenosine↗

PubMedDate not supplied

[Device for removing concrements from tubular organs].

Wide use of Dormia's loop for removing the concrements from tubular organs led to development of numerous designs of this device. Search for new designs serves one purpose: decrease the traumatism and risk of injury to the organ during the procedure. The new design is characterized by a longer length of service and is more reliable. It is free from the shortcomings of many known designs used for nonsurgical removal of the concrements from tubular organs, most frequently the ureters and its use is less traumatic.

Calculi↗

PubMedDate not supplied

[Diagnostic unit EKS-K1200].

The paper presents the block diagram of the unit, describes some assemblies and its operation as a whole, gives information on the software and technical data. The computer-based EKS-K 1200 unit integrates a pacemaker, a 12-channel electrocardiograph with a monitor, and a database.

Cardiac Pacing, Artificial↗