Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of 6-halo-(F-, Cl-, Br-, I-) and 6-alkoxy-(OMe-, OEt-) 9-(2,3-dideoxy-2-fluoro-beta-D-threopentofuranosyl) purines (F-ddN) have been synthesized and characterized with the objective of finding compounds which might be superior to existing drugs for the treatment of HIV in the central nervous system. These compounds, which contain lipophilic 6-substituents, were chosen as acid-stable prodrugs for the anti-HIV-active F-ddN, 9-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl) hypoxanthine (F-ddI), because of their potential to increase blood-brain-barrier penetration relative to F-ddI. All the new compounds were more lipophilic than the currently approved anti-AIDS drugs. Partition coefficient increases of 30- and 110-fold were achieved, relative to didanosine (ddI), for the 6-chloro- and 6-ethoxy analogues. 2'-Fluoro substitution abolished the pH 1, acid-catalyzed cleavage of the nucleoside glycosylic bond. However, pH 1, acid-catalyzed hydrolysis of the 6-fluoro substituent to produce F-ddI was observed to occur at a rate (t1/2 0.54 h) which was ca. 40-170 times faster than that of the other prodrugs. The utility of the F-ddNs as prodrugs for F-ddI depends upon their ability to act as substrates for adenosine deaminase. The relative rates of adenosine deaminase-catalyzed prodrug hydrolysis to F-ddI varied by a factor of > 25,000 with the 6-fluoro- and 6-ethoxy analogues reacting the fastest and slowest, respectively. All of the prodrugs possessed anti-HIV activity in the phytohemagglutinin-stimulated peripheral blood mononuclear cell test system and a qualitative correlation exists between prodrug anti-HIV activity and adenosine deaminase hydrolysis rates.
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PMID:Lipophilic, acid-stable, adenosine deaminase-activated anti-HIV prodrugs for central nervous system delivery. 2. 6-Halo and 6-alkoxy prodrugs of 2'-beta-fluoro-2',3'-dideoxyinosine. 770 21

As part of a research directed to the synthesis of novel isoniazid derivatives with potential activity on mycobacteria and HIV virus, the acetophenone-isonicotinoylhydrazones 3 and the 4-aryl-1-methoxy-1-(4-pyridyl)- 2,3-diaza-1,3-butadienes 5, obtained by reaction between isonicotinoylhydrazones and diazomethane, have been prepared and tested for such activities. Both classes of derivatives showed interesting growth inhibitory activity on non-tubercular mycobacteria, including the emerging M. avium. Such activity appears to be linked to fluorine and/or chlorine presence on benzene rings. In contrast, none of the compounds submitted to the anti-AIDS in vitro screening, displayed any protection against HIV-1 virus-induced cytopathic effect in T4-lymphocyte cell lines.
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PMID:Halogenated isoniazid derivatives as possible antimycobacterial and anti-HIV agents--III. 789 34

Legislation of the control of sexually transmitted diseases (STD) in the Federal Republic of Germany covers neither the complete spectrum of venereal diseases nor all population groups of high risk. We therefore investigated not only the classic STD but also some other STD, i.e. by serologic methods syphilis, HIV infection, hepatitis A, B, C, and herpes simplex genitalis, and by microbiological methods gonococci, chlamydiae, trichomonas, genital mycoplasmas, A-streptococci, B-streptococci, gram-negative enteric bacteria, anaerobic bacteria, staphylococci, listerias and yeasts. The cohorts of women living mainly monogamously and these of prostitutes were compared. They show some differences: There are remarkable differences in the prevalence of clinical symptoms, i.e. vaginal discharge, rubor, pruritus, and genital warts, between the two cohorts and depending on the season. Fluor, rubor, and pruritus were more frequently observed in mainly monogamous women than in prostitutes. Furthermore, the causative organisms of STD were isolated in different frequencies depending on the season particularly from mainly monogamous women. Furthermore, their frequencies depend on the age of the women. Gonococci, chlamydiae, trichomonas, genital mycoplasmas, B-streptococci and Staphylococcus aureus were significantly more isolated from prostitutes than from mainly monogamous women. But, on the other hand, candida and gram-negative enterobacteria are significantly more common in mainly monogamous women than in prostitutes. There are some correlations between clinical symptoms and organisms. The prevalence of syphilis, HIV-infection, hepatitis A, B, and C in the prostitutes were 7, 0.4, 3.5, 15, and 1.6%, respectively. The most intriguing observation is the decreasing incidence of causative organisms of STD in prostitutes during the three years of study. This phenomenon promises an improvement of the health standard of prostitutes by regular medical, microbiological, serological check-ups without charge.
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PMID:[Comparative clinical, microbiologic and serologic studies of the incidence of genital and para-genital infections in prostitutes and women with mainly monogamous relations]. 828 96

2'-beta-Fluoro-2',3'-dideoxyadenosine (F-ddA), an acid-stable, purine dideoxynucleoside with in vitro anti-HIV activity, has been selected by the NCI as a clinical trial candidate. A recent report that high, single doses of F-ddA produce cardiotoxicity in rats prompted the present investigation whose objective was to quantitate this effect and establish a relationship between this toxicity and F-ddA plasma concentrations. Microscopic examination of cardiac tissues for degenerative lesions established the effects of F-ddA and ddA on three iv schedules [daily x 1(2.5-250 mg/kg); daily x 5(125, 250 mg/kg), and BID x 1 (250 mg/kg)] as well as one oral schedule [BID x 1 (500 mg/kg) using 8- to 12-week old female Sprague-Dawley rats. For both F-ddA and ddA, the group mean severity of the cardiac lesions was dose-dependent and proportional to the measured plasma concentrations of the undeaminated parent drugs. F-ddI and ddI, were essentially nontoxic in this study (iv, 250 mg/kg, daily x 1 and daily x 5), since plasma concentrations exceeding 2 mM produced only minimal cardiac lesions. The cardiomyopathy of F-ddA was minimal to mild for all iv doses except 250 mg/kg (daily x 1) and usually was greater than that of ddA at any given dose. This is a consequence of the fact that F-ddA is deaminated 20 times more slowly than ddA, resulting in higher plasma concentrations of F-ddA relative to ddA at any given time for any given dose. Neither F-ddA nor ddA was more cardiotoxic on a repeated iv schedule (daily x 5) than when administered only once, suggesting that rat cardiotoxicity is related Cmax rather than total exposure. In this most sensitive species, the formation of cardiac lesions above the background level is associated with i.v. F-ddA administration when the F-ddA plasma concentration approaches 300 microM, 30-50 times the anticipated therapeutic level in humans.
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PMID:Acute cardiotoxicity of the Anti-HIV dideoxynucleoside, F-ddA, in the rat. 852 11

The authors describe a method to process induced sputum specimens for detection of Pneumocystis carinii which is simple, rapid and inexpensive. Induced sputum and bronchoalveolar lavage (BAL) were obtained within a 24-hour period from 41 patients who were HIV-positive and had pulmonary symptoms suspicious for P carinii pneumonia. Induced sputum or BAL fluid was placed into Saccomanno's fixative, blended, and centrifuged. The sediment was stained for P carinii cysts by a modified method with Fungi-Fluor Solution A (Polysciences, Warington, PA) and the Genetic Systems Pneumocystis carinii Immunofluorescence Antibody (Genetic Systems, Seattle, WA). The Genetic Systems stain on the BAL specimen was positive in 35 patients and was the standard for comparison. With a single induced sputum, the Genetic Systems stain detected 31 (89%) positive patients, whereas the Fungi-Fluor stain detected 21 (60%). The sensitivity for detecting P carinii cysts in induced sputum was significantly greater (P < 0.05) for the Genetic Systems stain.
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PMID:A rapid and inexpensive method for processing induced sputum for detection of Pneumocystis carinii. 856 Oct 88

2'-beta-Fluoro-2',3'-dideoxyadenosine (F-ddA) is an acid-stable purine dideoxynucleoside analog active against a wide spectrum of human immunodeficiency virus type 1 (HIV-1) and HIV-2 strains in vitro. F-ddA is presently undergoing a phase I clinical trial at the National Cancer Institute. We induced HIV-1 variants resistant to F-ddA by exposing wild-type HIV-1 (HIV-1LAI) to increasing concentrations of F-ddA in vitro. After 18 passages, the virus was fourfold less sensitive to F-ddA than HIV-1LAI. Sequence analyses of the passage 18 virus revealed changes in three amino acids in the reverse transcriptase (RT)-encoding region of the pol gene: P to S at codon 119 (P119S; present in 3 of 13 and 28 of 28 molecular clones before and after F-ddA exposure, respectively), V179D (0 of 13 and 9 of 28, respectively), and L214F (9 of 13 and 28 of 28, respectively). Drug sensitivity assays using recombinant infectious clones confirmed that P119S was directly responsible for the reduced sensitivity of HIV-1 to F-ddA. Various infectious clones with single or multiple amino acid substitutions conferring viral resistance against nucleoside RT inhibitors, including HIV-1 variants with multi-dideoxynucleoside resistance, were generally sensitive to F-ddA. The moderate level of resistance of HIV-1 to F-ddA, together with the lack of conferment of significant cross-resistance by the F-ddA-associated amino acid substitutions, warrants further investigation of F-ddA as a potential antiviral agent for use in treatment of HIV-1 infection.
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PMID:In vitro induction of human immunodeficiency virus type 1 variants resistant to 2'-beta-Fluoro-2',3'-dideoxyadenosine. 917 90

Fluorine nuclear magnetic resonance studies of the cleavage of peptides containing a 4-fluorophenylalanine (FPhe)-Pro bond have been performed in order to determine the conformational specificity of FPhe-Pro bond cleavage by pepsin. The peptides selected were substrates of HIV protease or of avian sarcoma virus protease, both of which have been reported to be cleaved specifically at X-Pro by pepsin as well as by the corresponding viral protease enzyme. By working at 0 degrees C, it was possible to separate kinetically cleavage and cis/trans isomerization. For the case of the protease substrate, Ser-Gln-Asn-FPhe-Pro-Ile-Val-Gln, cleavage was shown to be specific for the trans conformation. A value for the rate constant for hydrolysis of the trans peptide divided by the Michaelis constant, ktH/KMtrans = 0.3 min-1 mM-1 was obtained with this substrate, and the Michaelis constant appears to be considerably higher than the substrate concentration, 3.7 mM, used in the study. On a slower time scale, additional cleavages can readily be detected. For the avian leukemia virus protease substrate, Thr-Phe-Gln-Ala-FPhe-Pro-Leu-Arg-Glu-Ala, the cleavage was both slower and less specific. In addition to the primary cleavage at the FPhe-Pro site, cleavage also occurs at the Ala-FPhe bond on a somewhat slower time scale. In addition to the conformational specificity of the cleavage reaction, these results indicate that pepsin is a better model for HIV protease than for avian leukemia virus protease.
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PMID:Cleavage of the X-Pro peptide bond by pepsin is specific for the trans isomer. 934 Dec 12

A group of 5'-O-myristoyl analogue derivatives of FLT (2) were evaluated as potential anti-HIV agents that were designed to serve as prodrugs to FLT. 3'-Fluoro-2',3'-dideoxy-5'-O-(12-methoxydodecanoyl)thymidine (4) (EC50 = 3.8 nM) and 3'-fluoro-2',3'-dideoxy-5'-O-(12-azidododecanoyl)thymidine (8) (EC50 = 2.8 nM) were the most effective anti-HIV-1 agents. There was a linear correlation between Log P and HPLC Log retention time for the 5'-O-FLT esters. The in vitro enzymatic hydrolysis half-life (t1/2), among the group of esters (3-8) in porcine liver esterase, rat plasma and rat brain homogenate was longer for 3'-fluoro-2',3'-dideoxy-5'-O-(myristoyl)thymidine (7), with t1/2 values of 20.3, 4.6 and 17.5 min, respectively.
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PMID:Synthesis, in vitro anti-HIV activity, and biological stability of 5'-O-myristoyl analogue derivatives of 3'-fluoro-2',3'-dideoxythymidine (FLT) as potential bifunctional prodrugs of FLT. 970 20

2'-Fluorohexopyranosyl nucleosides 1a and 1b which contained a bioisosteric double bond and a fluorine were synthesized in 12 steps, starting from D-galactose. During diethylaminosulfur trifluoride (DAST) fluorination, retention of stereochemistry was observed through the participation of methoxy or chloro group at the 6-position of the purine base. The final nucleosides 1a and 1b were found to be inactive against HIV-1 and HSV-1,2.
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PMID:Synthesis and antiviral activity of 2'-fluorohexopyranosyl nucleosides. 987 54

Novel, lipophilic cycloSal triesters 4a-c and 5a-c were synthesized, respectively, from the ara- and ribo-configurated 2'-fluorinated-2', 3'-dideoxyadenosines 2 and 3. The cycloSal phosphotriesters were used as tools to study the effects of the two different sugar pucker conformations induced by two opposite configurations of the fluorine substituent at C2' of the dideoxyribose moiety. F-ara-ddA (2) is known to be an active anti-HIV agent, whereas the ribo-analogue 3 is inactive. Hydrolysis studies with the triester precursors 4a-c and 5a-c showed selective formation of the monophosphates of 2 and 3. The lipophilicity of the triester prodrugs was considerably increased by the cycloSal mask with respect to ddA (1), F-ara-ddA (2), and F-ribo-ddA (3). Phosphotriesters 4 and 5 proved to be completely resistant to ADA and AMPDA deamination. In parallel experiments, ribo-nucleoside 3 showed a 50-fold faster deamination rate relative to the ara-analogue 2. Against HIV in CEM cells, the phosphotriesters 4 proved to be 10-fold more potent than the parent nucleoside 2. Furthermore, the prodrugs 4 were active against MSV-induced transformation of C3H/3T3 fibroblasts, while 2 was inactive. More interestingly, the ribo-configurated phosphotriesters 5, prepared from the inactive F-ribo-ddA (3), showed a level of anti-HIV activity that was even higher than that of F-ara-ddA (2). Our findings clearly prove that the application of the cycloSal-pronucleotide concept to F-ribo-ddA (3) overcomes a metabolic blockade in the formation of the corresponding monophosphate.
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PMID:cycloSal-Pronucleotides of 2'-fluoro-ara- and 2'-fluoro-ribo-2',3'- dideoxyadenosine as a strategy to bypass a metabolic blockade. 1022 30


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