124 research outputs found
The anti-HIV activity of ADS-J1 targets the HIV-1 gp120
No full textRecent data suggest that heparin sulfates may bind to a CD4 induced epitope in the HIV-1 gp120 that constitutes the coreceptor binding site. We have studied the mechanism of action of ADS-J1, a non-peptidic compound selected by docking analysis to interact with gp41 and to interfere with the formation of N-36/C-34 complexes in sandwich ELISA experiments. We show that ADS-J1 blocked the binding of wild-type HIV-1 NL4-3 strain to MT-4 cells but not virus-cell binding of a polyanion-resistant virus. However, ADS-J1 blocked the replication of polyanion-resistant, T-20- and C34-resistant HIV-1, suggesting a second mechanism of action. Development of resistance to ADS-J1 on the polyanion-resistant HIV-1 led to mutations in gp120 coreceptor binding site and not in gp41. Time of addition experiments confirmed that ADS-J1, but not polyanions such as dextran sulfate or AR177, worked at a step that mimics the activity of an HIV coreceptor antagonist but prior to gp41-dependent fusion. We conclude that ADS-J1 may bind to the HIV coreceptor binding site as its mechanism of anti-HIV activity
A combination of molecular dynamics and docking calculations to explore the binding mode of ADS-J1, a polyanionic compound endowed with anti-HIV-1 activity
No full textThe HIV-1 entry process is an important target for the design of new pharmaceuticals for the multidrug therapy of AIDS. A lot of polyanionic compounds, such as polysulfonated and polysulfated, are reported in the literature for their ability to block early stages of HIV-1 replication. Several studies have been performed to elucidate the mechanism of the anti-HIV-1 activity of sulfated polysaccharides and polyanions in general, including binding to cell surface CD4 and interfering with the gp120−coreceptor interaction. Here, we show molecular modeling investigations on ADS-J1, a polyanionic compound with anti-HIV activity that is able to interfere with gp120−coreceptor interactions. Agreeing with experimental data, computer simulations suggested that the V3 loop of gp120 was the preferential binding site for ADS-J1 onto HIV-1. Moreover, mutations induced by the inhibitor significantly changed the stereoelectronic properties of the gp120 surface, justifying a marked drop in the affinity of ADS-J1 toward an ADS-J1-resistant HIV-1 strain
Data mining and mall users profile
No full textMarketing scholars have suggested a need for more empirical research on consumer response to malls, in order to have a better understanding of the variables that explain the behavior of the consumers. The segmentation methodology CHAID (Chi-square automatic interaction detection) was used in order to identify the profiles of consumers with regard to their activities at malls, on the basis of socio-demographic variables and behavioral variables (how and with whom they go to the malls). A sample of 790 subjects answered an online questionnaire. The CHAID analysis of the results was used to identify the profiles of consumers with regard to their activities at malls. In the set of variables analyzed the transport used in order to go shopping and the frequency of visits to centers are the main predictors of behavior in malls. The results provide guidelines for the development of effective strategies to attract consumers to malls and retain them there
Synthesis and biological investigation of S-aryl-S-DABO derivatives as HIV-1 inhibitors
No full textS-Aryl-S-DABO derivatives, a novel subclass of S-DABO anti-HIV-1 agents, were synthesized via Ullmann type reaction starting from the corresponding 2-thiouracils by the aid of microwave irradiation. The results of their evaluation as inhibitors of RT are reported together with their antiviral activity in cellular assays
Determinació de l’activitat antiviral de nous compostos inhibidors del VIH-1
No full textMés de 40 milions de persones en tot el món estan infectades pel virus de la immunodeficiència humana (VIH). Cinc milions es van infectar de nou i tres milions van morir pel Síndrome de la Immunodeficiència Adquirida (SIDA) el passat 2005. Des de mitjans de la dècada dels 90 el curs de la infecció pel VIH s'ha vist modificat per l'aparició del Tractament Antiretroviral de Gran Activitat (TARGA). La primera droga antiretroviral contra el VIH-1 va ser AZT, un anàleg de nucleòsid amb acció contra l'enzim transcriptasa inversa (RT) del virus. A més dels fàrmacs NRTIs (inhibidors de la transcriptasa inversa anàlegs de nucleòsid) trobem els NNRTIs (inhibidors de la transcriptasa inversa no anàlegs de nucleòsid) i els inhibidors de la proteasa (IPs). La combinació de dos o més fàrmacs d'aquestes famílies va donar lloc a la teràpia combinada del TARGA. Des de l'aparició del primer fàrmac anti-VIH, s'han anat desenvolupant nous agents capaços d'inhibir diferents etapes del seu cicle de replicació. Els últims fàrmacs en incorporar-se a la clínica han estat els inhibidors de la fusió de les membranes cel·lular i viral, com T-20, el maraviroc, un inhibidor del coreceptor CCR5 i els inhibidors de l’integració. En aquesta lluita per desenvolupar noves dianes d'actuació per inhibir l'infecció per VIH, són molts els grups que basen el seu treball en el desenvolupament de noves molècules amb un bon perfil d'inhibició de la infecció. En aquest treball de tesi doctoral es vol determinar el mecanisme d'acció de nous compostos dissenyats per a inhibir la infecció per VIH en diferents etapes del seu cicle, des de l'entrada del virus a la cèl·lula diana a etapes de transcripció inversa. A més es vol determinar si existeix una relació entre l'estructura de les diferents famílies de compostos analitzats i els seus perfils inhibitoris provats en assajos in vitro i in silico. Amb tots aquests estudis l'objectiu final és poder arribar a definir nous hits o molècules potencialment candidates a ser refinades per a acabar formant part de les noves teràpies contra el VIH en la clínica.
Per tal de poder dur a terme tots aquests estudis, primer de tot s'ha posat a punt un cribatge a gran escala de compostos mitjançant l'automatització de part de l'assaig. Un cop determinada l'activitat del compost a testar respecte un virus salvatge, es determina l'activitat d'aquest compost en virus amb mutacions que confereixen resistències a inhibidors ja coneguts emprats en la clínica i es realitzen diferents assajos per determinar-ne el lloc i mecanisme d'acció. Finalment, el conjunt d'anàlisis fetes amb els diferents compostos ens permetrà definir un perfil inhibitori per a cada compost i valorar-ne la seva validesa com a possible futur fàrmac anti-VIH.Over 40 million people worldwide are infected with human immunodeficiency virus (HIV). Five million people were new infected and three million were killed by the Acquired Immune Deficiency Syndrome (AIDS) on 2005. Since the mid 90's the course of HIV infection has been modified by the emergence of highly active antiretroviral therapy (HAART). The first antiretroviral drug against HIV-1 was AZT, a nucleoside analogue with action against the reverse transcriptase (RT) enzyme of the virus. In addition to NRTIs drugs (nucleoside reverse transcriptase inhibitors), there are NNRTIs (Non-nucleoside reverse transcriptase inhibitors) and protease inhibitors (PIs). The combination of two or more families of these drugs resulted in the combinated therapy of HAART. Since the appearance of the first anti-HIV drug, have been developing new agents capable of inhibiting various stages of its replication cycle. The latest drugs in joining the clinic were the membrane fusion inhibitors, like T-20, maraviroc, a CCR5 inhibitor and the integration imhibitors. In this struggle to develop new targets for action to inhibit HIV infection, many groups that base their work on the development of new molecules with a good infection inhibition profile. The aim of this doctoral thesis is to determine the mechanism of action of new compounds designed to inhibit HIV infection at different stages of their cycle, since the entry of the virus to target cell to reverse transcription. We also want to determine if there is a relationship between the structure of the different families of compounds analyzed and their tested inhibitory profiles in vitro and in silico. With all these studies the goal is to get hits or molecules to define new potential candidates to be refined to be part of the new HIV therapies in the clinic.
In order to perform these studies, first of all we have worked in a large-scale screening of compounds by automating part of the trial. Once determined the anti-HIV activity of the tested compounds against a wild virus, we determine the activity of these compounds against mutant viruses with resistance to known inhibitors used in the clinic to perform various tests to determine the site and mechanism of action of each compound. Finally, the set of tests made with different compounds will allow us to define an inhibitory profile for each compound and assess its validity as a possible future anti-HIV drug
Synthesis and Biological Properties of Novel 2-Aminopyrimidin-4(3H)-ones Highly Potent against HIV-1 Mutant Strains
No full textFollowing the disclosure of dihydro-alkoxy-, dihydro-alkylthio-, and dihydro-alkylamino-benzyl-oxopyrimidines (DABOs, S-DABOs, and NH-DABOs) as potent and selective anti-HIV-1 agents belonging to the non-nucleoside reverse transcriptase inhibitor (NNRTI) class, we report here the synthesis and biological evaluation of a novel series of DABOs bearing a N,N-disubstituted amino group or a cyclic amine at the pyrimidine-C2 position, a hydrogen atom or a small alkyl group at C5 and/or at the benzylic position, and the favorable 2,6-difluorobenzyl moiety at the C6 position (F2-N,N-DABOs). The new compounds were highly active up to the subnanomolar level against both wt HIV-1 and the Y181C mutant and at the submicromolar to nanomolar range against the K103N and Y188L mutant strains. Such derivatives were more potent than S-DABOs, NH-DABOs, and nevirapine and efavirenz were chosen as reference drugs. The higher inhibitor adaptability to the HIV-1 RT non-nucleoside binding site (NNBS) may account for the higher inhibitory effect exerted by the new molecules against the mutated RTs
Slow-, Tight-Binding HIV-1 Reverse Transcriptase Non-Nucleoside Inhibitors Highly Active against Drug-Resistant Mutants
No full text(Chemical Equation Presented) A new series of dihydro-alkylaminobenzyl- oxopyrimidines (N,N-DABOs) showing a broad activity spectrum against NNRTI-resistant mutants have been reported. Such compounds display a slow, tight binding to HIV-1 RT. © 2007 Wiley-VCH Verlag GmbH & Co. KGaA
A Multidisciplinary Approach for the Identification ofNovel HIV-1 Non-Nucleoside Reverse TranscriptaseInhibitors: S-DABOCs and DAVPs
No full textAmong the FDA approved drugs for the treatment of AIDS, non-nucleoside reverse transcriptase inhibitors (NNRTIs) are essential components of first-line anti-HIV-1 therapy because of the less-severe adverse effects associated with NNRTIs administration in comparison to therapies based on other anti-HIV-1 agents. In this contest, 3,4-dihydro-2-alkoxy-6-benzyl-4-oxypyrimidines (DABOs) have been the object of many studies aimed at identifying novel analogues endowed with potent inhibitory activity towards HIV-1 wild type and especially drug-resistant mutants. Accordingly, based on the encouraging results obtained from the biological screening of our internal collection of S-DABO derivatives, we started with the systematic functionalization of the pyrimidine scaffold to identify the minimal required structural features for RT inhibition. Herein, we describe how the combination of synthetic, biological, and molecular modeling studies led to the identification of two novel subclasses of S-DABO analogues: S-DABO cytosine analogues (S-DABOCs) and 4-dimethyamino-6-vinylpyrimidines (DAVPs)
Goigs al venerable P. Jaume Clotet i Fabrés, manresà i missioner, fill del Cor de Maria (Claretià)
No full textImpremta Minerva.
Exemplar 530 de 200 exemplars populars
Clinical impact of HIV-1 resistance against nonnucleoside analogue reverse transcriptase Inhibitors
No full textEls inhibidors de la transcriptassa inversa no anàlegs de nucleòsids (ITINAN) s'utilitzen sovint en el tractament antiretroviral (TAR) per la seva eficàcia i simplicitat. La resistència està causada per mutacions específiques a posicions de resistència. L'ús clínic dels ITINAN de primera generació (nevirapina i efavirenz) s'ha vist limitat pels efectes adversos, i la baixa barrera en front a la resistència, pel que s'han desenvolupat ITINAN de segona generació (etravirina i rilpivirina), ambdós recentment aprovats. No hem trobat relació entre interrupció o FV previs a nevirapina o efavirenz, i resposta a etravirina. El segon capítol analitza el impacte sobre rilpivirina de mutacions de resistència seleccionades en FV als altres ITINAN (nevirapina, efavirenz o etravirina) a 22 centres hospitalaris de España. Es va demostrar resistència a rilpivirina en el 20% de FV a ITINAN, més freqüent en FV a etravirina i nevirapina que a efavirenz. Les mutacions de resistència a rilpivirina més freqüents van ser Y181C, K101E/P, H221Y i E138A/G/K. E138K/M184I, la combinació mes freqüentment seleccionada amb rilpivirina en naives, va estar absent en aquesta població pretractada. L100I i V108I van ser significativament més freqüents en fracassos a efavirenz. Contràriament, Y181C/I, V106A, H221Y i F227L ho van ser amb nevirapina. Finalment el tercer capítol estima la eficàcia de un règim de simplificació de TAR amb nevirapina, tenofovir i emtricitabina/lamivudina, realitzat a la nostra Unitat a Barcelona. No es van aïllar patrons de mutacions inesperats en els FV. A les 48 setmanes el 90% de malalts tenien una càrrega viral 50 còpies/mL, el FV va ser infreqüent, i 25 (7.4%) pacients van suspendre el tractament per toxicitat. Els factors associats amb FV a l'anàlisi multivariant van ser drogadicció intravenosa, temps amb càrrega viral indetectable abans de la simplificació, nombre de NRTIs i NNRTIs rebuts, i les interrupcions no programades de tractaments previs amb nevirapina o efavirenz. En base a aquestes dades s'hauria de desaconsellar el reinici del TAR amb nevirapina, tenofovir i emtricitabina/lamivudina en interrupcions no programades del TAR, encara que la càrrega viral sigui indetectable al moment de la suspensió. Inesperadament, hem trobat una taxa significativament més elevada de FV amb lamivudina que amb emtricitabina amb aquesta combinació, així com una major selecció de M184V. Aquests resultats suggereixen precaució en la substitució de emtricitabina per lamivudina, al menys en règims basats en nevirapina i tenofovirNon-nucleoside reverse transcriptase inhibitors (NNRTIs) are popular components of antiretroviral therapy due to their efficacy and simplicity. Resistance is caused only by specific mutations at drug-resistance positions. Despite its proven efficacy, the clinical use of first-generation NNRTIs (nevirapine and efavirenz) has been limited by side effects and low barrier to resistance. To overcome these limitations, a second-generation of NNRTIs has been developed including etravirine and rilpivirine, both recently approved. Rilpivirine also depicts a low barrier to resistance development. We found no relationship between prior interruption or VF with nevirapine or efavirenz and response to etravirine. The second chapter assesses the RAMs selected in subjects failing NNRTI-based treatments (with nevirapine, efavirenz or etravirine) at 22 clinics in Spain and the potential impact on rilpivirine's activity. Rilpivirine resistance was recognized in 20% of these patients, more commonly following etravirine or nevirapine failures than efavirenz. The most prevalent rilpivirine RAMs in subjects failing other NNRTIs were Y181C, K101E/P, H221Y and E138A/G/K. E138K/M184I, the most frequently selected combination in initial treatment with rilpivirine, was absent in this treatment-experienced population. L100I and V108I were significantly more frequent in efavirenz failures. Conversely, Y181C/I, V106A, H221Y and F227L were more prevalent in nevirapine ones. Finally, the third chapter estimates the effectiveness of a nevirapine-based switch regimen in subjects with suppressed viremia, combined with tenofovir and emtricitabine (or lamivudine). The analysis has been done in our clinic in Barcelona. No unexpected RAMs or patterns of RAMs were selected in treatment failures to this regimen. At week 48, nearly 90% of the subjects had HIV-1 RNA 50 copies/mL, VF was uncommon, and 25 (7.4%) subjects discontinued the treatment due to toxicity. Factors independently associated with VF in multivariate analysis were intravenous drug use, time with undetectable viral load before the switch, number of prior NRTIs or NNRTIs, and previous nevirapine or efavirenz unscheduled interruptions. Reinitiation of nevirapine plus tenofovir plus emtricitabine (or lamivudine) should be discouraged in subjects experiencing unplanned treatment interruptions, even with an undetectable plasma viral load at the time of treatment withdrawal. Unexpectedly, we found a significantly higher rate of VF with lamivudine instead of emtricitabine with this regimen, with a significantly higher selection of M184V as well. Our findings suggest caution against substituting emtricitabine for lamivudine, at least in nevirapine- and tenofovir-based regimens
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