Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001175 (AIDS)
 120,706 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Isoniazid is a frontline drug used in the treatment of tuberculosis (TB). Isoniazid is a prodrug, requiring activation in the mycobacterial cell by the catalase/peroxidase activity of the katG gene product. TB kills two million people every year and the situation is getting worse due to the increase in prevalence of HIV/AIDS and emergence of multidrug-resistant strains of TB. Arylamine N-acetyltransferase (NAT) is a drug-metabolizing enzyme (E.C. 2.1.3.5). NAT can acetylate isoniazid, transferring an acetyl group from acetyl coenzyme A onto the terminal nitrogen of the drug, which in its N-acetylated form is therapeutically inactive. The bacterium responsible for TB, Mycobacterium tuberculosis, contains and expresses the gene encoding the NAT protein. Isoniazid binds to the NAT protein from Salmonella typhimurium and we report here the mode of binding of isoniazid in the NAT enzyme from Mycobacterium smegmatis, closely related to the M. tuberculosis and S. typhimurium NAT enzymes. The mode of binding of isoniazid to M. smegmatis NAT has been determined using data collected from two distinct crystal forms. We can say with confidence that the observed mode of binding of isoniazid is not an artifact of the crystallization conditions used. The NAT enzyme is active in mycobacterial cells and we propose that isoniazid binds to the NAT enzyme in these cells. NAT activity in M. tuberculosis is likely therefore to modulate the degree of activation of isoniazid by other enzymes within the mycobacterial cell. The structure of NAT with isoniazid bound will facilitate rational drug design for anti-tubercular therapy.
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PMID:Binding of the anti-tubercular drug isoniazid to the arylamine N-acetyltransferase protein from Mycobacterium smegmatis. 1572 51

TMC114 (darunavir) is a promising clinical inhibitor of HIV-1 protease (PR) for treatment of drug resistant HIV/AIDS. We report the ultra-high 0.84 A resolution crystal structure of the TMC114 complex with PR containing the drug-resistant mutation V32I (PR(V32I)), and the 1.22 A resolution structure of a complex with PR(M46L). These structures show TMC114 bound at two distinct sites, one in the active-site cavity and the second on the surface of one of the flexible flaps in the PR dimer. Remarkably, TMC114 binds at these two sites simultaneously in two diastereomers related by inversion of the sulfonamide nitrogen. Moreover, the flap site is shaped to accommodate the diastereomer with the S-enantiomeric nitrogen rather than the one with the R-enantiomeric nitrogen. The existence of the second binding site and two diastereomers suggest a mechanism for the high effectiveness of TMC114 on drug-resistant HIV and the potential design of new inhibitors.
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PMID:Ultra-high resolution crystal structure of HIV-1 protease mutant reveals two binding sites for clinical inhibitor TMC114. 1696 36

HIV-1 protease is an effective target for designing drugs against AIDS, and structural information about the true transition state and the correct mechanism can provide important inputs. We present here the three-dimensional structure of a bi-product complex between HIV-1 protease and the two cleavage product peptides AETF and YVDGAA. The structure, refined against synchrotron data to 1.65 A resolution, shows the occurrence of the cleavage reaction in the crystal, with the product peptides still held in the enzyme active site. The separation between the scissile carbon and nitrogen atoms is 2.67 A, which is shorter than a normal van der Waal separation, but it is much longer than a peptide bond length. The substrate is thus in a stage just past the G'Z intermediate described in Northrop's mechanism [Northrop DB (2001) Acc Chem Res 34:790-797]. Because the products are generated in situ, the structure, by extrapolation, can give insight into the mechanism of the cleavage reaction. Both oxygens of the generated carboxyl group form hydrogen bonds with atoms at the catalytic center: one to the OD2 atom of a catalytic aspartate and the other to the scissile nitrogen atom. The latter hydrogen bond may have mediated protonation of scissile nitrogen, triggering peptide bond cleavage. The inner oxygen atoms of the catalytic aspartates in the complex are 2.30 A apart, indicating a low-barrier hydrogen bond between them at this stage of the reaction, an observation not included in Northrop's proposal. This structure forms a template for designing mechanism-based inhibitors.
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PMID:Crystal structure of HIV-1 protease in situ product complex and observation of a low-barrier hydrogen bond between catalytic aspartates. 1711 69

Availability of a reliable oxygen (O2) supply is critical for hospitals in developing countries. The AIDS pandemic that is associated with severe pulmonary infections has further enhanced this problem. Today in 2006, even though a number of financially viable solutions adapted to conditions in developing countries are available, lack of oxygen is still a cause of death in Africa including in some capital cities. Hospitals in industrial countries have wall outlets supplied from liquid O2 storage tanks (-183 degrees C). However this solution requires advanced cryogenic technology with storage as well as transportation of liquid O2. In developing countries, O2 is supplied from pressurized O2 cylinders (200 bars) sometimes stored in racks to supply wall outlets but more often moved from bed to bed as needed. This solution is expensive because of the cost of transportation on poor roads in all areas outside capital cities. Frequent supply shortages lead to major disruptions in care quality. Properly maintained O2 concentrators can provide a highly effective low-cost easy-to-use solution for health facilities in developing countries. The pressure swing adsorption (PSA) process based on reversible nitrogen adsorption is a reliable economical autonomous oxygen production process ideally suited to hospitals in developing countries. It can be used to supply wall outlets or fill cylinders. Return on investment is achieved within one to two years.
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PMID:[The problem of oxygen in developing countries]. 1728 38

We present a 40-year-old woman who presented to the genitourinary medicine department with a two-year history of recurrent non-painful vulval lumps. She was in a stable relation with one male sexual partner over the preceding 20 years and her sexual health screen was negative. Clinical examination of these lumps was suggestive of anogenital warts for which she has been treated on numerous occasions over the last two-year-period with liquid nitrogen cryotherapy and podophyllotoxin 0.15% cream. As the lumps were not responding to conventional wart treatment, a biopsy from these lesions was performed. The histological appearance showed focal fibrin thrombus formation within dilated vascular channels consistent of a subepidermal cavernous haemangioma. This case demonstrates that the clinical diagnosis of anogenital warts is not always straightforward. It highlights the importance of obtaining a tissue diagnosis from the resistant or atypically looking warty lesions to avoid making the wrong diagnosis.
Int J STD AIDS 2008 Mar
PMID:Be wary, this is not a case of vulval warts! 1839 68

HIV-1 protease is an effective target for design of different types of drugs against AIDS. HIV-1 protease is also one of the few enzymes that can cleave substrates containing both proline and nonproline residues at the cleavage site. We report here the first structure of HIV-1 protease complexed with the product peptides SQNY and PIV derived by in situ cleavage of the oligopeptide substrate SQNYPIV, within the crystals. In the structure, refined against 2.0-A resolution synchrotron data, a carboxyl oxygen of SQNY is hydrogen-bonded with the N-terminal nitrogen atom of PIV. At the same time, this proline nitrogen atom does not form any hydrogen bond with catalytic aspartates. These two observations suggest that the protonation of scissile nitrogen, during peptide bond cleavage, is by a gem-hydroxyl of the tetrahedral intermediate rather than by a catalytic aspartic acid.
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PMID:X-ray structure of HIV-1 protease in situ product complex. 1870 47

Piperidinylpyrimidine derivatives, previously prepared as inhibitors of TNF-alpha production, were evaluated for their inhibitory activity against HIV-1 LTR activation. Some of these derivatives inhibited activation of HIV-1 LTR-directed CAT gene expression induced by PMA in Jurkat cells. In this report, we describe SAR in this series of compounds and show that the 3,4-methylenedioxybenzoyl (piperonyloyl) group on the nitrogen of piperidine and lipophilic substitution at the C(6)-position of pyrimidine are important for this inhibitory activity. Some of the synthesized compounds also inhibited HIV-1 LTR transactivation induced by viral protein Tat. These results suggest that piperidinylpyrimidines are useful as potent AIDS therapeutics that directly inhibit HIV-1 LTR activation and indirectly suppress TNF-alpha production.
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PMID:Novel piperidinylpyrimidine derivatives as inhibitors of HIV-1 LTR activation. 1892 11

This work analyzes multiple new reaction pathways which originate from intramolecular reactions of activated alkynes with the appropriately positioned multifunctional hemiaminal moiety. Combination of experimental substituent effects with Natural Bond Orbital (NBO) analysis revealed that alkyne polarization controls partitioning between these cascades. A particularly remarkable transformation leads to the formation of six new bonds at the two alkyne carbons due to complete disassembly of the alkyne moiety and formal insertion of a nitrogen atom between the two acetylenic carbons of the reactant. This reaction offers a new synthetic approach for the preparation of polycyclic aromatic amides with a number of possible applications in molecular electronics. Another of the newly discovered cascades opens access to substituted analogues of Sampangine alkaloids which are known for their antifungal and antimycobacterial activity against AIDS-related opportunistic infection pathogens.
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PMID:An unexpected rearrangement that disassembles alkyne moiety through formal nitrogen atom insertion between two acetylenic carbons and related cascade transformations: new approach to Sampangine derivatives and polycyclic aromatic amides. 1958 68

The mutation G48V in HIV-1 protease is a major resistance mutation against the drug saquinavir. Recently, G48V mutation is found to co-exist with the mutation C95F in AIDS patients treated with saquinavir. We report here the three-dimensional crystal structure of G48V/C95F tethered HIV-1 protease/saquinavir complex. The structure indicates following as the possible causes of drug resistance: (1) loss of direct van der Waals interactions between saquinavir and enzyme residues PHE-53 and PRO-1081, (2) loss of water-mediated hydrogen bonds between the carbonyl oxygen atoms in saquinavir and amide nitrogen atoms of flap residues 50 and 1050, (3) changes in inter-monomer interactions, which could affect the energetics of domain movements associated with inhibitor-binding, and (4) significant reduction in the stability of the mutant dimer. The present structure also provides a rationale for the clinical observation that the resistance mutations C95F/G48V/V82A occur as a cluster in AIDS patients.
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PMID:Insights into the mechanism of drug resistance: X-ray structure analysis of G48V/C95F tethered HIV-1 protease dimer/saquinavir complex. 2047 72

Many new phenothiazines exhibit promising anticancer and antibacterial activities, reversal of multidrug resistance and potential treatment in Alzheimer's, Creutzfeldt-Jakob and AIDS diseases. Their synthesis may proceed through a stage of the Smiles rearrangement and may lead to different products: cyclic phenothiazines (rearranged or not), cyclic side-products of isosteric structures and non-cyclic products when the ring-closure processes did not occur. The TLC method was found suitable for detection of new modified phenothiazines (being tri-, tetra- and pentacyclic azaphenothiazines with hydrogen, alkyl, dialkylaminoalkyl, aryl and heteroaryl substituents at the thiazine nitrogen atom and in a few cases additional substituents in the benzene ring) during their synthesis. The natural fluorescence of phenothiazines and azaphenothiazines under irradiation of UV light of 365nm is very characteristic and becomes useful additional analytical information of these compounds. The spots of azaphenothiazines were also distinguished from the spots of substrates and side-products by giving color reactions with the visualizing reagents: sulfuric acid in ethanol, concentrated nitric acid and citric acid in acetic anhydride. The combination of the separation (the R(F) values) and the spot color detection (as the native fluorescence and the results of the usage of visualizing reagents) facilitated the identifications of new azaphenothiazines in the reaction mixtures containing also other compounds. This paper is the first attempt of the determination of new azaphenothiazines by TLC method preceding the identification by spectroscopic methods. It facilitates the separation of the proper fraction in column chromatography and preparative TLC.
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PMID:Thin-layer chromatographic detection of new azaphenothiazines. 2142 90


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