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

Phosphonoformate (foscarnet) is a pyrophosphate (PP(i)) analogue and a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), acting through the PP(i) binding site on the enzyme. HIV-1 RT can unblock a chain-terminated DNA primer by phosphorolytic transfer of the terminal residue to an acceptor substrate (PP(i) or a nucleotide such as ATP) which also interacts with the PP(i) binding site. Primer-unblocking activity is increased in mutants of HIV-1 that are resistant to the chain-terminating nucleoside inhibitor 3'-azido-3'-deoxythymidine (AZT). We have compared the primer-unblocking activity for HIV-1 RT containing various foscarnet resistance mutations (K65R, W88G, W88S, E89K, S117T, Q161L, M164I, and the double mutant Q161L/H208Y) alone or in combination with AZT resistance mutations. The level of primer-unblocking activity varied over a 150-fold range for these enzymes and was inversely correlated with foscarnet resistance and directly correlated with AZT resistance. Based on published crystal structures of HIV-1 RT, many of the foscarnet resistance mutations affect residues that do not make direct contact with the catalytic residues of RT, the incoming deoxynucleoside triphosphate (dNTP), or the primer-template. These mutations may confer foscarnet resistance and reduce primer unblocking by indirectly decreasing the binding and retention of foscarnet, PP(i), and ATP. Alternatively, the binding position or orientation of PP(i), ATP, or the primer-template may be changed in the mutant enzyme complex so that molecular interactions required for the unblocking reaction are impaired while dNTP binding and incorporation are not.
 ...
PMID:Relationship between 3'-azido-3'-deoxythymidine resistance and primer unblocking activity in foscarnet-resistant mutants of human immunodeficiency virus type 1 reverse transcriptase. 1274 70

Objective: The Authors report their experience of Cytomegalovirus (CMV) retinitis therapy in HIV patients, using Ganciclovir and Foscarnet in monotherapy. They also evaluate the reliability of the Polymerase Chain Reaction (PCR) through the qualitative technique as an index of active disease. Methods: 18 patients suffering from CMV retinitis were treated: Ganciclovir was administered at a dosage of 10 mg/kg b.w./day and Foscarnet at 180 mg/kg b.w./day, both of them for 21 days during the induction phase. During the mantainance phase the former was administered at 5 mg/kg b.w./day and the latter at 90 mg/kg b.w./day for 5 days a week. Results: Both the drugs induced the stabilization or regression of the lesions. There was however a relapse with both therapies. We did not observe a significant difference either in the entity and the duration of the stabilization or in the survival from diagnosis time. Finally the PCR method was not helpful in the diagnosis of CMV retinitis.
 ...
PMID:[Observations about the treatment of Cytomegalovirus retinitis in patients with HIV infection using Ganciclovir and Foscarnet] 1276 86

A new enzyme-labile group called S-acyl-3-thiopropyl group (SATP) has been synthesized from allylic esters of phosphonate. After demonstration of the enzyme-labile character of the SATP in cellular extracts, it has been introduced onto the phosphonate moiety of PFA (Foscarnet) to obtain potential lipophilic prodrugs. To ponder the lipophilicity of the triesters of PFA, esters of monomethylether of polyethyleneglycols and of thioglycerol were introduced on the PFA carboxylate moiety. The SATP groups were introduced in an attempt to deliver PFA after bioactivation inside the cells. The PFA prodrugs were evaluated in vitro for their activity against human immunodeficiency viruses (HIV-1 and HIV-2).
 ...
PMID:Synthesis and in vitro evaluation of S-acyl-3-thiopropyl prodrugs of Foscarnet. 1501 12

This paper describes the first example of combination of non-nucleoside reverse transcriptase inhibitors such as TSAO derivatives and foscarnet (PFA) in a single molecule through a labile covalent ester bond. The essential criteria in the design of these hybrids [TSAO-T]-[PFA] was to explore if the conjugation of foscarnet with the highly lipophilic TSAO derivative may facilitate the penetration of the conjugates through the cell membrane and if the hybrids escape extracellular hydrolysis and regenerate the parent inhibitors intracellulary. Several [TSAO-T]-[PFA] conjugates proved markedly inhibitory to HIV-1. Some of them also showed potent activity against PFA-resistant HIV-1 strains but fewer had detectable inhibitory activity against TSAO-resistant HIV-1 strains. These results indicated a pivotal role of the TSAO component of the hybrid but not the PFA component in the activity of the conjugates. Moreover, stability studies of the [TSAO-T]-[PFA] conjugates demonstrated that the compounds were stable in PBS whereas some of the conjugates regenerated the parent inhibitors in extracts from CEM cells.
 ...
PMID:Hybrids of [TSAO-T]-[foscarnet]: The first conjugate of foscarnet with a non-nucleoside reverse transcriptase inhibitor through a labile covalent ester bond. 1518 38

The pyrophosphate (PPi) analogue phosphonoformic acid (PFA or foscarnet) inhibits the reverse transcriptase (RT) of the human immunodeficiency virus type 1 (HIV-1); however, the mechanisms of drug action and resistance remain elusive. Here we studied the effects of the translocational status of HIV-1 RT on drug binding and inhibition of DNA synthesis. We identified "hot spots" for inhibition during active elongation. Site-specific footprinting analyses revealed that the corresponding complexes exist predominantly in the pre-translocational state. The sensitivity to PFA is significantly reduced with sequences that show a bias toward the post-translocational state. Binding studies showed that PFA stabilizes selectively the complex in the pre-translocated configuration. These findings are consistent with a Brownian ratchet model of polymerase translocation. The enzyme can rapidly shuttle between pre- and post-translocated states. The bound inhibitor acts like a pawl of a ratchet and prevents the forward motion of HIV-1 RT, whereas the bound nucleotide binds to the post-translocated complex and prevents the reverse motion. The proposed mechanisms of RT translocation and drug action are consistent with the PFA-resistant phenotypes. We show that certain sequences and the PFA-resistant E89K mutant diminishes the stability of the pre-translocated complex. In these cases, the enzyme is seen at multiple positions around the 3' end of the primer, which provides a novel mechanism for resistance. These findings validate the pre-translocated complex as a target for the development of novel, perhaps less toxic and more potent inhibitors that block HIV-1 RT translocation.
 ...
PMID:The pyrophosphate analogue foscarnet traps the pre-translocational state of HIV-1 reverse transcriptase in a Brownian ratchet model of polymerase translocation. 1714 4

Extracts from twenty two medicinal plants popularly used in preparing traditional remedies in Kenya were screened for activity against the HIV-1 reverse transcriptase. The screening procedure involved the use of tritium labeled thymidine triphosphate as the enzyme substrate and polyadenylic acid.oligodeoxythymidylic acid [poly(rA).p(dT)12-18] as the template primer dimer. Foscarnet was used as a positive control in these experiments. At a concentration of 100 microg/ml, extracts from eight of these plants showed at least 50 per cent reverse transcriptase inhibition. This activity was arbitrarily considered as significant. This indicates that there is the probability that some antiretroviral compounds could be identified and isolated from materials from these plants.
 ...
PMID:Evaluation of the HIV-1 reverse transcriptase inhibitory properties of extracts from some medicinal plants in Kenya. 1729 48

Foscarnet (phosphonoformate trisodium salt), an antiviral used for the treatment of HIV and herpes virus infections, also acts as an activator or inhibitor of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). Interaction of the drug with 11 CA isozymes has been investigated kinetically, and the X-ray structure of its adduct with isoform I (hCA I-foscarnet complex) has been resolved. The first CA inhibitor possessing a phosphonate zinc-binding group is thus evidenced, together with the factors governing recognition of such small molecules by a metalloenzyme active site. Foscarnet is also a clear-cut example of modulator of an enzyme activity which can act either as an activator or inhibitor of a CA isozyme.
 ...
PMID:Phosph(on)ate as a zinc-binding group in metalloenzyme inhibitors: X-ray crystal structure of the antiviral drug foscarnet complexed to human carbonic anhydrase I. 1731 45

Foscarnet, licenced by Astra pharmaceutical products, is a pyrophosphate analogue that selectively inhibits replication of viruses in infected cells. It inhibits in vitro the replication of all herpes viruses, including human cytomegalovirus (HCMV) at concentrations of 100 to 300 mumol/l and has a dose-related inhibitory effect on HIV-1 virus, influenza virus and hepatitis B virus. It does not require intra-cellular phosphorylation for antiviral activity. Oral bioavailability of foscarnet is low (12-22%), and foscarnet must be administered intravenously. It is mainly eliminated unchanged by the kidneys. Mean half-life in plasma ranges from 3.4 to 5 h. For acute therapy, the currently recommended regimen is 60 mg/kg t.i.d. or 90-100 mg/kg b.i.d. In AIDS patients, foscarnet is an effective treatment of HCMV retinitis. Healing or stabilisation of lesions is obtained in 85-95% of patients after 2 weeks or 3 weeks therapy. For HCMV gastrointestinal disease, complete or partial response rates of 57-95% have been reported with foscarnet. The optimal maintenance dosage of foscarnet necessary in CMV infections in AIDS patients remains to be clearly established. Data from small samples size studies have shown that foscarnet decreased significantly circulating levels of HIV antigen in AIDS patients with HCMV disease. Foscarnet is an effective treatment for acyclovir-resistant herpes simplex virus and for acyclovir-resistant varicella-zoster virus (40 mg/kg every 8 h). In patients with immunosuppression not HIV-related HCMV infections, particularly interstitial pneumonia in transplant recipients, experience with foscarnet is limited. The major adverse effect of foscarnet is reversible renal dysfunction, due to acute tubular toxicity. In may be partially prevented by hyperhydratation during the treatment. Fluctuations in serum calcium and phosphore levels, with both increase and decrease are also frequent adverse reactions. Most clinical symptoms are related to decrease in ionized calcium levels. Hyperphosphatemia, a clinically benign phenomenom, reflects the incorporation of foscarnet in bone. Penile ulcerations have been described and may result from mococutaneous direct toxicity of foscarnet eliminated in urine. Although relapses frequently occur after a few months of maintenance therapy, foscarnet that shows a marked activity against HCMV in vitro, has allowed important progress in therapy of HCMV infections in AIDS patients.
 ...
PMID:Pharmacology and clinical use of foscarnet. 1861 71

To prepare a new antiviral duplex drug linking Zidovudine (AZT) and Foscarnet (PFA) via a lipophilic octadecylglycerol residue we condensed 1-O-4-monomethoxytrityl-3-O-octadecyl-sn-glycerol-2-hydrogenphosphonate obtained from 3-O-octadecyl-sn-glycerol with AZT by the phosphonate method. The purified condensation product was de-tritylated resulting in 3'-azido-3'-deoxythymidylyl-(5'-->2-O)-3-O-octadecyl-sn-glycerol, followed by treatment with (ethoxycarbonyl)phosphoric dichloride. The resulting 3'-azido-3'-deoxy-thymidylyl-(5'-->2)-3-O-octadecyl-sn-glycerol-1-O-(ethoxycarbonyl)phosphonate was purified by preparative RP-18 column chromatography. The antiviral duplex drug 3'-azido-3'-deoxythymidylyl-(5'-->2-O)-3-O-octadecyl-sn-glycerol-1-O-phosphonoformate trisodium salt (AZT-lipid-PFA) was obtained after alkaline cleavage of the phosphonoformate ethylester residue. The overall yield of the five step synthesis performed at gram scale was about 30%. According to a supposed pathway AZT-lipid-PFA could be cleaved to yield a mixture of different antiviral compounds such as AZT, AZT-5'-monophosphate, octadecylglycerol-AZT, PFA and octadecylglycerol-PFA, possibly producing additive and/or synergistic antiviral effects. In vitro studies showed that the duplex drug exhibits antiviral activities against HIV and especially against drug-resistant strains and clinical isolates of HSV and HCMV. The E(50) values of AZT-lipid-PFA against HIV ranged between 170 and 200 nM. The half-maximal inhibitory doses (IC(50)) against highly acyclovir (ACV)-resistant HSV isolates determined by a plaque reduction assay ranged between 1.87 and 4.59 microM. Using ganciclovir (GCV)-sensitive, GCV resistant and drug cross-resistant HCMV strains the IC(50)-values of AZT-lipid-PFA were between 2.78 and 1.18 microM. With regard to PFA, the IC(50)-value of AZT-lipid-PFA determined on a multi-drug-resistant HCMV strain was about 90-fold lower than that of PFA, demonstrating the superior antiviral effect of the duplex-drug.
 ...
PMID:Synthesis and in vitro activities of a new antiviral duplex drug linking Zidovudine (AZT) and Foscarnet (PFA) via an octadecylglycerol residue. 1901 Jun 84

Foscarnet-induced genital erosions have been reported in patients treated for HIV-related herpesvirus infections in adults. We report the case of a boy with penile erosions associated with foscarnet therapy in the setting of umbilical cord blood transplantation (CBT).
 ...
PMID:Penile erosions associated with foscarnet therapy in a child. 2060 54


<< Previous 1 2 3 4 5 6 Next >>