Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.49 (reverse transcriptase)
 31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Our studies have shown that the acyclic nucleotide analogues PMEA and HPMPC are able to penetrate into cells and are then activated to mono- and diphosphate derivatives. The latter correspond to triphosphate analogues and presumably serve an important role in the biological activity exerted by these antiviral agents. In support of this idea, the inhibitory effect of PMEApp on HIV reverse transcriptase has been demonstrated with both RNA and DNA template-primer systems. Further studies will be undertaken to determine the effect of HPMPCpp on viral DNA polymerases. Whereas the metabolism of PMEA in CEM cells gives rise to only PMEAp and PMEApp, additional metabolites were obtained in MRC-5 cells; the identity of these metabolites remains to be determined. In the case of HPMPC, a third metabolite was obtained in addition to HPMPCp and HPMPCpp, which has been tentatively assigned as a phosphate-choline adduct by analogy with activation of cytosine-based nucleoside derivatives. The metabolism of HPMPC was unchanged between uninfected and infected cells, indicating that viral enzymes are not necessary for the activation of HPMPC. The long intracellular half-lives of the HPMPC metabolites may have implications for the antiviral efficacy of this compound. The persistence of activated metabolites suggests that infrequent dosing may be possible due to a prolonged antiviral effect. Our results on the effectiveness of infrequent dosing schedules with HPMPC in the treatment of HSV 2 infections in mice support this hypothesis. It is also possible that HPMPCp-choline may serve as a reservoir for HPMPC and therefore for the presumed active metabolite HPMPCpp.
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PMID:Biochemical pharmacology of acyclic nucleotide analogues. 207 30

The target protein (enzyme) with which antiviral agents interact determines their antiviral activity spectrum. Based on their activity spectrum, antiviral compounds could be divided into the following classes: (1) sulfated polysaccharides (i.e., dextran sulfate), which interact with the viral envelope glycoproteins and are inhibitory to a broad variety of enveloped viruses (i.e., retro-, herpes-, rhabdo-, and arenaviruses): (2) SAH hydrolase inhibitors (i.e., neplanocin A derivatives), which are particularly effective against poxvirus, (-)RNA viruses (paramyxovirus, rhabdovirus), and (+/-)RNA virus (reovirus); (3) OMP decarboxylase inhibitors (i.e., pyrazofurin) and CTP synthetase inhibitors (i.e., cyclopentenylcytosine), which are active against a broad range of DNA, (+)RNA, (-)RNA, and (+/-)RNA viruses; (4) IMP dehydrogenase inhibitors (i.e., ribavirin), which are also active against various (+)RNA and (-)RNA viruses and, in particular, ortho- and paramyxoviruses; (5) acyclic guanosine analogs (i.e., ganciclovir) and carbocyclic guanosine analogs (i.e., cyclobut-G), which are particularly active against herpesviruses (i.e., HSV-1, HSV-2, VZV, CMV); (6) thymidine analogs (i.e., BVDU, BVaraU), which are specifically active against HSV-1 and VZV because of their preferential phosphorylation by the virus-encoded thymidine kinase; (7) acyclic nucleoside phosphonates (i.e., HPMPA, HPMPC, PMEA, FPMPA), which, depending on the structure of the acyclic side chain, span an activity spectrum from DNA viruses (papova-, adeno-, herpes-, hepadna-, and poxvirus) to retroviruses (HIV); (8) dideoxynucleoside analogs (i.e., AZT, DDC), which act as chain terminators in the reverse transcriptase reaction and thus block the replication of retroviruses as well as hepadnaviruses; and (9) the TIBO, HEPT, and other TIBO-like compounds, which interact specifically with the reverse transcriptase of HIV-1 and thus block the replication of HIV-1, but not of HIV-2 or any other retrovirus.
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PMID:Antiviral agents: characteristic activity spectrum depending on the molecular target with which they interact. 843 May 18

Acyclovir is an effective drug for the treatment of HSV and VZV infections, which after phosphorylation to the triphosphate, inhibits viral DNA polymerase. Acyclovir has low oral bioavailability, therefore prodrugs have been developed, and the L-valyl ester, valaciclovir, recently has been licensed for the treatment of shingles. Ganciclovir is used against CMV, and famciclovir, a lipophilic prodrug of penciclovir, is marketed for shingles. The acyclic nucleoside phosphonates are active against thymidine kinase-resistant viral strains. Promising analogs are PMEA (in clinical trial for the treatment of AIDS) and (S)-HPMPC (good in vivo activity against HSV, VZV, CMV, and EBV). Oligonucleotides incorporating acyclic nucleosides at the 3'-and 5'-ends, or constituted of amino acyclic nucleosides, are resistant to cleavage by nucleases and may be useful in antisense and/or antigene therapy. HEPT is active against HIV-1: It binds in a hydrophic pocket on reverse transcriptase, rather than in the polymerase active site. Some acyclic nucleosides are potent inhibitors of purine and pyrimidine nucleoside phosphorylase. These compounds may have a therapeutic niche in combination therapy with antiviral and anticancer nucleosides, and in the treatment of diseases involving the T-cell.
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PMID:Acyclic nucleosides as antiviral compounds. 873 25

This article describes several approaches to a selective therapy of virus infections: (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU [brivudin]) for the therapy of herpes simplex virus type 1 and varicella-zoster virus infections: (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC [cidofovir]) for the therapy of various DNA virus (i.e., herpesvirus, adenovirus, papillomavirus, polyomavirus, and poxvirus) infections; 9-(2-phosphonylmethoxyethyl)adenine (PMEA [adefovir]) for the therapy of retrovirus, hepadnavirus, and herpesvirus infections; (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) for the therapy and prophylaxis of retrovirus and hepadnavirus infections; and nonnucleoside reverse transcriptase inhibitors (NNRTIs), such as tetrahydroimidazo[4,5,1-jk][1,4]-benzodiazepin-2(IH)-one and -thione (TIBO), 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT), alpha-anilinophenylacetamide (alpha-APA), and 2',5'bis-O-(tert-butyldimethylsilyl)-3'-spiro-5"-(4"-amino-1",2"-oxat hiole- 2",2"-dioxide)pyrimidine (TSAO) derivatives, and thiocarboxanilides for the treatment of human immunodeficiency virus type 1 (HIV-1) infections. For the clinical use of NNRTIs, some guidelines have been elaborated, such as starting treatment with combinations of different compounds at sufficiently high concentrations to effect a pronounced and sustained suppression of the virus. Despite the diversity of the compounds described here and the different viruses at which they are targeted, they have a number of characteristics in common. As they interact with specific viral proteins, the compounds achieve a selective inhibition of the replication of the virus, which, in turn, should be able to develop resistance to the compounds. However, as has been established for the NNRTIs, the problem of viral resistance may be overcome if the compounds are used from the start at sufficiently high doses, which could be reduced if different compounds are combined. For HIV infections, drug treatment regimens should be aimed at reducing the viral load to such an extent that the risk for progression to AIDS will be minimized, if not avoided entirely. This may result in a real "cure" of the disease but not necessarily of the virus infection, and in this sense, HIV disease may be reduced to a dormant infection, reminiscent of the latent herpesvirus infections. Should virus replication resume after a certain time, the armamentarium of effective anti-HIV and anti-herpesvirus compounds now available, if applied at the appropriate dosage regimens, should make the virus return to its dormant state before it has any chance to damage the host. It is unlikely that this strategy would eradicate the virus and thus "cure" the viral infection, but it definitely qualifies as a cure of the disease.
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PMID:In search of a selective antiviral chemotherapy. 933 68

Restriction fragment length polymorphism analysis was used to differentiate recent field viruses of canine distemper virus (CDU) from vaccine strains. Virus genomes were amplified by using reverse transcriptase-polymerase chain reaction in part of the haemagglutinin gene. After digestion with EcoRV, the PCR products of recent field isolates were cut into two fragments that differ from the uncut form of old strains including all of vaccine strains. This method could be applied to fresh or stored brains, spleens and peripheral blood mononuclear cells of infected dogs. This molecular approach is useful for determining the causative agent of postvaccinated CDV infection.
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PMID:Molecular identification of a recent type of canine distemper virus in Japan by restriction fragment length polymorphism. 985 1

(S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (HPMPC [cidofovir]) and (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine (HPMPA) are potent inhibitors of a variety of DNA viruses. These drugs possess a 3'-hydroxyl equivalent which could support chain extension from an incorporated drug molecule. HPMPC and HPMPA were initially reported to lack activity against human immunodeficiency virus type 1 (HIV-1); more recent results have shown that the octadecyloxyethyl (ODE) and hexadecyloxypropyl (HDP) esters of HPMPA are potent inhibitors of the virus. We have synthesized the ODE esters of a series of (S)-[3-hydroxy-2-(phosphonomethoxy)propyl] (HPMP) nucleosides, including HPMPC, HPMP-guanine (HPMPG), HPMP-thymine (HPMPT), and HPMP-diaminopurine (HPMPDAP), as well as the ODE ester of the obligate chain terminator (S)-9-[3-methoxy-2-(phosphonomethoxy)-propyl]adenine (MPMPA). All compounds except ODE-HPMPT were inhibitors of HIV-1 replication at low nanomolar concentrations. These compounds were also inhibitors of the replication of HIV-1 variants that are resistant to various nucleoside reverse transcriptase (RT) inhibitors at concentrations several times lower than would be expected to be achieved in vivo. To investigate the mechanism of the antiviral activity, the active metabolites of HPMPC and HPMPA were studied for their effects on reactions catalyzed by HIV-1 RT. Incorporation of HPMPC and HPMPA into a DNA primer strand resulted in multiple inhibitory effects exerted on the enzyme and showed that neither compound acts as an absolute chain terminator. Further, inhibition of HIV-1 RT also occurred when these drugs were located in the template strand. These results indicate that HPMPC and HPMPA inhibit HIV-1 by a complex mechanism and suggest that this class of drugs has a broader spectrum of activity than previously shown.
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PMID:Inhibition of HIV-1 by octadecyloxyethyl esters of (S)-[3-hydroxy-2-(phosphonomethoxy)propyl] nucleosides and evaluation of their mechanism of action. 2189 14