Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The antiviral activity of 6-0-butanoylcastanospermine (MDL 28,574) [50% inhibitory concentration (IC50: 1.1 microM)] in JM cells infected with a recent isolate of HIV-1 (GB8), was compared with other inhibitors of glycoprotein-processing enzymes. N-butyldeoxynojirimycin (BuDNJ), deoxynojirimycin (DNJ), castanospermine (CAST) or the reverse transcriptase inhibitor 2'3'-dideoxycytidine (ddC) had activities of 56, 560, 29 and 0.1 microM, respectively. MDL 28,574 was at least 50 times more active than BuDNJ and less active but better tolerated in cell culture than ddC, two compounds currently undergoing clinical trials. The CAST derivative showed good protection in H9 cells infected with HIV-1 (RF; IIIB; U455), and HIV-2 (ROD), although the potency was less than that seen in the JM/GB8 system. HIV-1 glycoproteins, gp160 and gp120, synthesized in H9 cells chronically infected with HIV-1 (RF) and treated with MDL 28,574, were characterized by an increase in relative molecular weight of approximately 7-8000 kD. The ratio of gp120 to gp160 was markedly reduced in treated cells and provided further evidence that cleavage of the gp160 precursor molecule is a major consequence of the inhibition of glycoprotein processing. The intracellular target for MDL 28,574 was verified as alpha-glucosidase-I of the processing enzymes by the analysis of high-glucose glycopeptides recovered from treated mouse cells. This activity correlated with the antiviral effect observed against the growth of a mouse retrovirus, Moloney murine leukemia virus (MOLV), in mouse cells.
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PMID:6-0-butanoylcastanospermine (MDL 28,574) inhibits glycoprotein processing and the growth of HIVs. 165 79

Human T-lymphoblastoid cells H9, CEM and CEM-clone 5 were selected for growth in RPMI 1640 supplemented with transferrin 5 micrograms/ml, insulin 5 micrograms/ml and sodium selenite 5 ng/ml. After 40 days of adaptation to serum-free medium, these cells displayed growth, morphology, and expression of CD4 similar to serum-supplemented cultures. Infection of these cells with two strains of HIV-1 (LAV and NDK) and a strain of HIV-2 (ROD) was as efficient in serum-free as in serum-supplemented medium as demonstrated by reverse transcriptase activity in the culture supernatants of infected cells. Furthermore, HIV-induced cytopathogenicity was observed in serum-free cultures, demonstrating that both HIV infection and cytopathic effect did not require the presence of serum components. Electron microscopy showed that mature viral particles were produced from infected cells cultured in serum-free medium. Finally, the ability of monoclonal antibody OKT4 A to inhibit infection by HIV-1 LAV but not by HIV-1 NDK was the same with and without serum in the culture medium, demonstrating that both CD4-dependent and CD4-independent infections can occur in the total absence of serum. Human T-lymphoblastoid cells adapted for growth in serum-free medium provide therefore a complementary tool for the study of HIV infection and cytopathogenicity under defined conditions.
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PMID:Human T-lymphoblastoid cells selected for growth in serum-free medium provide new tools for study of HIV replication and cytopathogenicity. 172 73

In vitro evaluation of a large chemical library of pharmacologically acceptable prototype compounds in a high-capacity, cellular-based screening system has led to the discovery of another family of human immunodeficiency virus type 1 (HIV-1) inhibitors. Through optimization of a lead compound, several alpha-anilinophenylacetamide (alpha-APA) derivatives have been identified that inhibit the replication of several HIV-1 strains (IIIB/LAI, RF, NDK, MN, HE) in a variety of host cell types at concentrations that are 10,000- to 100,000-fold lower than their cytotoxic concentrations. The IC50 of the alpha-APA derivative R 89439 for HIV-1 cytopathicity in MT-4 cells was 13 nM. The median 90% inhibitory concentration (IC90) in a variety of host cells was 50-100 nM. Although these alpha-APA derivatives are active against a tetrahydroimidazo [4,5,1-jk][1,4]benzodiazepin-2(1H)-thione-(TIBO)-resistant HIV-1 strain, they do not inhibit replication of HIV-2 (strains ROD and EHO) or simian immunodeficiency virus (strains Mac251, mndGB1, and agm3). An HIV-1 strain containing the Tyr181-->Cys mutation in the reverse transcriptase region displayed reduced sensitivity. alpha-APA derivative R 89439 inhibited virion and recombinant reverse transcriptase of HIV-1 but did not inhibit that of HIV-2. Reverse transcriptase inhibition depended upon the template/primer used. The relatively uncomplicated synthesis of R 89439, its potent anti-HIV-1 activity, and its favorable pharmacokinetic profile make R 89439 a good candidate for clinical studies.
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PMID:Potent and highly selective human immunodeficiency virus type 1 (HIV-1) inhibition by a series of alpha-anilinophenylacetamide derivatives targeted at HIV-1 reverse transcriptase. 768 Apr 76

A series of omega-undecanoic amides of lup-20(29)-en-28-oic acid derivatives were synthesized and evaluated for activity in CEM 4 and MT-4 cell cultures against human immunodeficiency virus type 1 (HIV-1) strain IIIB/LAI. The potent HIV inhibitors which emerged, compounds 5a, 16a, and 17b, were all derivatives of betulinic acid (3beta-hydroxylup-20(29)-en-28-oic acid). No activity was found against HIV-2 strain ROD. Compound 5a showed no inhibition of HIV-1 reverse transcriptase activity with poly(C).oligo(dG) as template/primer, nor did it inhibit HIV-1 protease. Additional mechanistic studies revealed that this class of compounds interfere with HIV-1 entry in the cells at a postbinding step.
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PMID:Betulinic acid derivatives: a new class of human immunodeficiency virus type 1 specific inhibitors with a new mode of action. 867 41

We evaluated the cytotoxic effects of various human immunodeficiency virus (HIV-1) reverse transcriptase inhibitors (zidovudine, didanosine, zalcitabine, stavudine, and nevirapine) on HIV-1-infected and uninfected T cell lines. Among the compounds, only stavudine (not the others) proved to be more cytotoxic to MOLT-4/IIIB cells (MOLT-4 cells chronically infected with HIV-1) than to uninfected MOLT-4 cells. Its 50% cytotoxic concentrations were 59.8 and 2.2 microM for MOLT-4 and MOLT-4/IIIB cells, respectively. Stavudine was also more cytotoxic to CEM/ROD (CEM cells chronically infected with HIV type 2) than to uninfected CEM cells. Microscopic analysis revealed that stavudine induced apoptosis in MOLT-4/IIIB cells. Apparent chromatin condensation in the nucleus was observed by electron microscopy. Furthermore, a DNA fragmentation ladder was detected by agarose gel electrophoresis. Addition of thymidine to the culture medium could rescue the cells from stavudine-induced apoptosis. The expression of anti-apoptotic protein Bcl-2 was partially downregulated in MOLT-4/IIIB cells after treatment with stavudine. This downregulation was not identified in MOLT-4 cells. These results indicate that stavudine selectively induces apoptosis in HIV-1-infected T cells and may have potential as a novel strategy for effective chemotherapy of the acquired immune deficiency syndrome (AIDS).
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PMID:Stavudine selectively induces apoptosis in HIV type 1-infected cells. 900 5

HIV-Nef protein supports viral infectivity prior to proviral integration. This requires Nef to be present before the expression of viral genes and suggests its delivery as part of the virion. We report here that the Nef proteins of HIV-2-HOM and HIV-2-ROD are associated with the virion. After the separation of pelleted virus in a 20-60% sucrose density gradient, both proteins cosedimented with the virion-associated reverse transcriptase (RT) activity at a density characteristic of retroviral particles. Whereas Nef-2-ROD was present in the virion only as the full-length protein, HIV-2-HOM appeared as 32 and 35 kDa isoforms. The smaller isoform is identical in molecular weight to the protein expected from proteolytic cleavage of full-length Nef-2-HOM by the virion-based protease. Virion-association of Nef helps to explain the recently redefined biological function of this regulatory protein.
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PMID:Evidence for the association of Nef protein with HIV-2 virions. 902 83

We report the development of a new group of nonnucleoside reverse transcriptase inhibitors (NNRTIs). One of the most active congeners of this series of 1,1,3-trioxo-2H,4H-thieno[3,4-e] [1,2,4]thiadiazine (TTD) derivatives, i.e., 2-(3-fluorobenzyl)-4-cyanomethylen-l,1,3-trioxo-2H,4H- thieno [3,4-e] [1,2,4] thiadiazine) (QM96639) was found to inhibit human immunodeficiency virus (HIV) type 1 [HIV-1 (IIIB)] replication in MT-4 cells at a concentration of 0.09 microM. This compound was toxic for the host cells only at a 1,400-fold higher concentration. The TTD derivatives proved effective against a variety of HIV-1 strains, including those that are resistant to 3'-azido-3'-deoxythymidine (AZT), but not against HIV-2 (ROD) or simian immunodeficiency virus (SIV/ MAC251). HIV-1 strains containing the L100I, K103N, V106A, E138K, Y181C, or Y188H mutations in their reverse transcriptase (RT) displayed reduced sensitivity to the compounds. Their cross-resistance patterns correlated with that of nevirapine. 2-Benzyl-4-cyanomethylen-1,1,3-trioxo-2H,4H-thieno[3,4-e] [1,2,4]thiadiazine (QM96521) enhanced the anti-HIV-1 activity of AZT and didanosine in a subsynergistic manner. HIV-1-resistant virus containing the V179D mutation in the RT was selected after approximately six passages of HIV-1 (IIIB) in CEM cells in the presence of different concentrations of QM96521. From structure-activity relationship analysis of a wide variety of TTD derivatives, a number of restrictions appeared as to the chemical modifications that were compatible with anti-HIV activity. Modelling studies suggest that in contrast to most other NNRTIs, but akin to nevirapine, QM96521 does not act as a hydrogen bond donor in the RT-drug complex.
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PMID:1,1,3-Trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazine (TTD) derivatives: a new class of nonnucleoside human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitors with anti-HIV-1 activity. 951 42

Inhibition of HIV-1 replication by differently substituted spirocyclopropyl compounds has been evaluated. Compound 21 showed a moderate activity (EC50 ranging from 2.3 to 5.8 micrograms/ml) against different HIV-1 strains (IIIB, RF, NDK, and an AZT-resistant strain) in different cell lines (MT-4 and C-8166 cells), while it was cytotoxic at 77.7 micrograms/ml, resulting in a selectivity index of 34. This compound was inactive against HIV-2 (ROD) and SIV (MAC251). From "time-of-addition" experiments compound 21, like AZT, appeared to inhibit HIV-1 at the reverse transcriptase step.
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PMID:Inhibition of human immunodeficiency virus type (HIV-1) replication by some diversely functionalized spirocyclopropyl derivatives. 1036 1

The anti-HIV activity of a novel series of 1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazines (TTDs) has been described. The compounds were synthesized via Curtius rearrangement of appropriate sulfamoylcarboxy azides which, in turn, were prepared from known starting materials. Several 4-substituted-2-benzyl-derivatives were found to selectively inhibit human immunodeficiency virus type 1 [HIV-1 (IIIB)] replication in MT-4 and CEM cells. These TTDs were also effective against other strains of HIV-1 (RF, HE, MN, NDK), including those that are resistant to AZT, but not against HIV-2 (ROD) or simian immunodeficiency virus [SIV(MAC251)] at subtoxic concentrations. Some of the test compounds exhibited antiviral activity against L100I RT mutant virus, but significantly lost antiviral activity against K103N, V106A, E138K, Y181C and Y188H RT mutant viruses. Compounds 6d, 6f and 6g were inhibitory to HIV-1 RT at concentrations that rank between 16.4 and 59.8 microM (nevirapine: IC50 = 4.5 microM against HIV-1 RT). Inhibition of HIV-1 RT by compound 6g was purely non-competitive with respect to the natural substrate (dGTP), which is in agreement with the nature of inhibition shown by other NNRTIs such as nevirapine and delarvidine. A structure-activity relationship was established for the anti-HIV activity of these heterocyclic compounds. TTDs represent a new chemical class of non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs).
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PMID:Synthesis and anti-HIV activity of 1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazines (TTDs): a new family of HIV-1 specific non-nucleoside reverse transcriptase inhibitors. 1065 85

The antiviral activity for primary isolates of human immunodeficiency virus (HIV) type 1 of a combination of methylene blue and light irradiation was investigated, in comparison with their virucidal effects on laboratory-adapted HIV-1. The antiviral mechanism was evaluated in terms of reverse transcriptase activity and viral RNA in the same viral stock. Despite a marked reduction in RNA (>3.07 Log(10)) and infectivity (6.10 Log(10)) under conditions of 1 microM methylene blue and 5 J/cm(2) irradiation when HIV-1(HTLV-IIIB) as a representative HIV-1 was employed, relatively little degradation of the viral envelope (0.20 Log(10)) and reverse transcriptase activity (1.52 Log(10)) was observed. Because no difference in the reduction of infectivity was found between primary isolates and laboratory-adapted HIV-1 (including HIV-2(ROD)), the antiviral mechanism of methylene blue photosensitization may be similar for all types of HIVs. Methylene blue photosensitization seems to deprive HIVs of infectivity, mainly due to RNA damage, and weak structural and functional damage of viral proteins.
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PMID:Elucidation of the HIV-1 virucidal mechanism of methylene blue photosensitization and the effect on primary isolates. 1107 69


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