Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human immunodeficiency virus (HIV) is a lentivirus which replicates within critical cells of the immune system, particularly CD4+ T-cells and monocyte/macrophages, leading to a progressive loss of helper T-cells and profound immunosuppression. This condition is known as the acquired immunodeficiency syndrome (AIDS). A rational screening strategy was adopted to evaluate new anti-HIV agents. Primary in vitro evaluation of antiviral compounds and studies of the relationship between structure and antiviral activity were carried out in a CD4+ T-cell line (MT-4). These cells develop a cytopathic effect (CPE) within a few days after infection. Initially, protection against the HIV-induced cytopathic effect as well as the MT-4 host cell cytotoxicity was determined by a highly automated evaluation system. Promising lead compounds emerging from these studies were then further investigated for their anti-HIV properties in other target cells and against different HIV-1 and HIV-2 strains. This strategy allowed the identification of several potent and selective inhibitors of HIV replication in vitro. Following the 3'-azidothymidine (AZT) lead, we synthesized and evaluated other 2',3'-dideoxynucleoside analogues with modifications in the base and/or sugar moiety. Based on their selectivity indexes in vitro, several congeners of this group, including 2',3'-thymidine (ddeThd, D4T) and 5-chloro-3'-fluoro-2',3'-dideoxyuridine (FddClUrd), seem at least as promising as AZT. From a series of phosphonylmethoxyalkylpurines and -pyrimidines, 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP) emerged as a new class of broad-spectrum anti-retrovirus agents. Sulfated polysaccharides and sulfated polymers represent another class of compounds achieving high therapeutic indexes in vitro. Comparative studies allowed to define the structural requirements for anti-HIV activity. Finally, a rational screening strategy allowed the identification of tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepine-2(1H)-one and -thione (TIBO) derivatives which represent a complete new class of anti-HIV-1 agents.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Development of new potent and selective agents against HIV (human immunodeficiency virus). 181 6

The acyclic nucleoside phosphonate analogues (HPMPA, HPMPC, PMEA, FPMPA) show great promise for the treatment of infections with such important human pathogens as adeno, pox (vaccinia) and hepadna (hepatitis B) viruses (HPMPA), herpes (herpes simplex, varicella-zoster, cytomegalo, Epstein-Barr) viruses (HPMPC), and retro (human immunodeficiency) viruses (PMEA, FPMPA). All these compounds seem to be targeted at the viral DNA polymerase, with which they interact, as either competitive inhibitors or alternative substrates (or chain terminators), following their intracellular phosphorylation to the diphosphoryl derivatives. Of particular interest is the prolonged anti-viral action, lasting for several days or even weeks, that has been noted both in vitro and in vivo after a single administration of the acyclic nucleoside phosphonates.
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PMID:Chemotherapy of the acquired immune deficiency syndrome (AIDS): acyclic nucleoside phosphonate analogues. 182 10

9-(2-Phosphonylmethoxyethyl)adenine (PMEA) is a new antiviral compound with activity against herpes simplex virus (HSV) and retroviruses including human immunodeficiency virus. Although it has been suggested that the anti-HSV action of PMEA is through inhibition of the viral DNA polymerase via the diphosphorylated metabolite of PMEA (PMEApp), no conclusive evidence for this has been presented. We report that in cross-resistance studies, a PMEA-resistant HSV variant (PMEAr-1) was resistant to phosphonoformic acid, a compound which directly inhibits the HSV DNA polymerase. In addition, phosphonoformic acid-resistant HSV variants with defined drug resistance mutations within the HSV DNA polymerase gene were resistant to PMEA. Furthermore, the HSV DNA polymerase purified from PMEAr-1 was resistant to PMEApp in comparison with the enzyme from the parental virus. Moreover, PMEA inhibited HSV DNA synthesis in cell culture. These results provide strong evidence that HSV DNA polymerase is the major target for the anti-viral action of PMEA. Further studies showed that HSV DNA polymerase incorporated PMEApp into DNA in vitro, while the HSV polymerase-associated 3'-5' exonuclease was able to remove the incorporated PMEA. Thus, the inhibition of HSV DNA polymerase by PMEApp appears to involve chain termination after its incorporation into DNA.
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PMID:Herpes simplex virus-specified DNA polymerase is the target for the antiviral action of 9-(2-phosphonylmethoxyethyl)adenine. 184 64

9-(2-Phosphonylmethoxyethyl)adenine (PMEA) is a potent and selective inhibitor of the in vitro replication of a number of retroviruses, including HIV-1 and HIV-2, simian immunodeficiency virus (SIV), simian AIDS-related virus (SRV), feline immunodeficiency virus (FIV) and Moloney murine sarcoma virus (MSV). PMEA causes a dose-dependent suppression of the induction of anti-SIVmacgp120 antibodies in SIV mac-infected rhesus monkeys. Complete suppression of anti-SIVmacgp120 antibodies was achieved in SIV-infected animals treated with PMEA at 2 x 10 or 2 x 5 mg/kg per day for 29 days. No toxic side-effects were noted during this treatment period. Antibodies against SIVmac gp120 appeared 1-2 weeks after PMEA treatment was stopped, but the antibody titre reached in these animals was significantly lower than in the SIVmac-infected animals who had not been treated with PMEA. Our data strongly suggest that PMEA should be pursued for its potential in the treatment of AIDS and other retrovirus infections.
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PMID:9-(2-Phosphonylmethoxyethyl)adenine (PMEA) effectively inhibits retrovirus replication in vitro and simian immunodeficiency virus infection in rhesus monkeys. 205 58

A series of 9-(phosphonoalkyl)purines, which are analogues of 9-[2-(phosphonomethoxy)ethyl]purines (guanine, PMEG, 1; adenine, PMEA, 2), were synthesized. The analogues were tested for activity against herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), human cytomegalovirus (HCMV), Rauscher murine leukemia virus (R-MuLV), and human immunodeficiency virus type 1 (HIV-1). With variations in the length of the alkyl chain, the optimal activity was achieved with two carbons between the purine base and the phosphonomethoxy functionality. Despite the structural similarity and the close pKa2 value of 8 to that of PMEG, no phosphorylation of 8 was observed by the bovine brain guanylate kinase. Since all isosteric analogues of PMEG (7-9) were not inhibitory against HSV-1 and HSV-2, the presence of the 3'-oxygen atom in the PME purines proved critical for anti-HSV activity. Introduction of the 1'-methyl group on the PMEG side chain significantly reduced its anti-HSV activity. Analogue 11, which is a mimic of the phosphate by incorporation of the alpha,alpha-difluoro carbon, was ineffective against HSV-1 and HSV-2. These results suggest that the structural requirements of PME purines for anti-HSV activity appear to be very strict.
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PMID:Acyclic purine phosphonate analogues as antiviral agents. Synthesis and structure-activity relationships. 215 12

The acyclic purine nucleoside analogue 9-(2-phosphonomethoxyethyl)adenine [PMEA; formerly referred to as 9-(2-phosphonylmethoxyethyl)adenine] is a potent and selective inhibitor of human immunodeficiency virus replication in vitro and of Moloney murine sarcoma virus-induced tumor formation in mice. In the latter system PMEA has stronger antiretroviral potency and selectivity than 3'-azido-3'-thymidine (AZT). We have now investigated the effect of the drug in cats infected with the feline immunodeficiency virus (FIV). In vitro, PMEA was found to efficiently block FIV replication in feline thymocytes (50% effective dose, 0.6 microM). When administered to cats at doses of 20, 5, or 2 mg/kg per day, PMEA caused a dose-dependent suppression of FIV replication and virus-specific antibody production. Seropositive field cats with signs of opportunistic infection (gingivitis, stomatitis, and diarrhea) showed clinical improvement during PMEA therapy (5 mg/kg per day) and recurrence of the disease after treatment was discontinued. Thus, FIV infection in cats is an excellent model to test the efficacy of selective anti-human immunodeficiency virus agents in vivo.
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PMID:Suppression of feline immunodeficiency virus infection in vivo by 9-(2-phosphonomethoxyethyl)adenine. 215 2

9-(2-Phosphonylmethoxyethyl)adenine (PMEA), a potent inhibitor of human immunodeficiency virus (HIV), caused a dose-dependent suppression of tumor formation, and mortality associated therewith, in 6-day-old NMRI mice inoculated intracerebrally with Moloney murine sarcoma virus (MSV). Even at a dose as low as 1 mg/kg/day, PMEA effected a significant delay in tumor formation. When evaluated in parallel with PMEA, 3'-azido-2',3'-dideoxythymidine (AZT) conferred a comparable tumor-inhibitory effect at a 5- to 10-fold higher dose than PMEA. Prolonged treatment of MSV-infected mice with PMEA resulted in long-term survivors without apparent signs of tumor development. In view of the propensity of HIV to spread to the central nervous system (CNS), the marked activity shown by PMEA against experimental retrovirus infection of the brain in mice points to its potential in the treatment of AIDS and other retrovirus infections of the CNS.
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PMID:Inhibitory effects of 9-(2-phosphonylmethoxyethyl)adenine and 3'-azido-2',3'-dideoxythymidine on tumor development in mice inoculated intracerebrally with Moloney murine sarcoma virus. 230 39

Different treatment schedules have been investigated when evaluating the inhibitory effect of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and 3'-azido-2',3'-dideoxythymidine (AZT) on the replication of human immunodeficiency virus type I (HIV-I) in MT-4 cells, transformation of C3H/3T3 cells by Moloney murine sarcoma virus (MSV), and MSV-induced tumor formation in newborn NMRI mice. Shortening the exposure time of HIV-I-infected MT-4 cells to PMEA or AZT led to an increase in the selectivity index of both compounds. PMEA proved markedly more efficient in suppressing MSV-induced tumor formation in mice when administered as a single dose on the day of infection than when these doses were spread over 2, 4 or 7 administrations within 1 week after the virus infection. This was not observed when the total dose of AZT was fractionated. While the infrequent dosage regimen increased the anti-retrovirus activity of PMEA, it did not increase its toxicity for the host. This unique property makes PMEA an attractive candidate for the treatment of retrovirus infections, including AIDS.
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PMID:Anti-retrovirus activity of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) in vivo increases when it is less frequently administered. 238 80

The replication of human immunodeficiency virus in vitro is inhibited by some acyclic adenosine derivatives, such as 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)-2,6-diaminopurine [(S)-HPMPDAP], as well as by 3'-azido-3'-deoxythymidine (AZT). In a human T-lymphocyte cell line, C3, at 6 days postinfection, the 50% effective concentration (EC50) of AZT was 0.02 microM and the 90% effective concentration (EC90) was 0.33 microM; for PMEA, the EC50 was 1.9 microM and the EC90 was 27 microM. For (S)-HPMPDAP, the EC50 was 2.3 microM and the EC90 was 36 microM. Most combinations of AZT and PMEA produced a synergistic effect. In the T-cell line C3, the combination indices for 50 to 90% inhibition of virus replication ranged from 0.25 to 1.25. Combinations of PMEA (or other members of this group) with AZT appear to be worth further study for the possible treatment of acquired immunodeficiency syndrome.
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PMID:Susceptibility of human immunodeficiency virus type 1 replication in vitro to acyclic adenosine analogs and synergy of the analogs with 3'-azido-3'-deoxythymidine. 247 34

The murine model of acquired immunodeficiency disease was used to evaluate both the antiretroviral and antiherpetic activities of the acyclic nucleotide analog 9-(2-phosphonylmethoxyethyl)adenine (PMEA). The antiretroviral activity of PMEA was compared with that of azidothymidine (AZT) in mice receiving the drug either immediately after infection or at late times in disease progression. Both AZT (oral, 30 mg/kg) and PMEA (parenteral, 25 and 5 mg/kg) were effective in slowing the development of disease when administered daily beginning on the day of infection. In contrast, neither drug alone was effective in modifying disease outcome when administered several weeks after viral infection. Human recombinant alpha interferon (rhuIFN alpha-B/D at 5 x 10(7) U/kg) was also ineffective when administered late in the course of disease. However, when administered in combination, both alpha interferon and PMEA (25 mg/kg) were able to suppress disease progression even when treatment was initiated as late as 3 weeks postinfection. Mice that were immunocompromised due to LP-BM5 virus infection were highly susceptible to acute (lethal) infection with herpes simplex virus type 1, whereas their immunocompetent littermates were not. PMEA was as effective as acyclovir in the treatment of opportunistic herpes simplex virus type 1 infections in LP-BM5 virus-infected mice. Thus, like AZT, PMEA was effective against retrovirus infection, and, like acyclovir, PMEA was effective against herpes simplex virus type 1 infection. This gives PMEA the unique potential of being useful in the treatment of opportunistic herpes simplex virus infections as well as the underlying retroviral disease.
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PMID:9-(2-Phosphonylmethoxyethyl)adenine in the treatment of murine acquired immunodeficiency disease and opportunistic herpes simplex virus infections. 248 11


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