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)

Novel low molecular weight spirodiketopiperazine derivatives which potently inhibit R5 human immunodeficiency virus type 1 (HIV-1) infection through their antagonistic effects on CCR5 were identified. One such compound E913 (M(r) 484) specifically blocked the binding of macrophage inflammatory protein-1alpha (MIP-1alpha) to CCR5 (IC(50) 0.002 microm) and MIP-1alpha-elicited cellular Ca(2+) mobilization (IC(50) approximately 0.02 microm). E913 potently inhibited the replication of laboratory and primary R5 HIV-1 strains as well as various multidrug-resistant monocyte/macrophage tropic (R5) HIV-1 at IC(50) values of 0.03 to 0.06 microm. E913 was inactive against T cell tropic (X4) HIV-1; however, when combined with a CXCR4 antagonist AMD-3100, E913 potently and synergistically inhibited the replication of dualtropic HIV-1 and a 50:50 mixture of R5 and X4 HIV-1. Antagonism in anti-HIV-1 activity was not seen when E913 was combined with the reverse transcriptase inhibitor zidovudine or protease inhibitors. E913 proved to compete with the binding of antibodies to CCR5 which recognize the C-terminal half of the second extracellular loop (ECL2B) of CCR5. E913 and its analogs are acid-resistant and orally bioavailable in rodents. These data warrant that spirodiketopiperazine derivatives be further developed as potential therapeutics for HIV-1 infection.
 ...
PMID:Novel low molecular weight spirodiketopiperazine derivatives potently inhibit R5 HIV-1 infection through their antagonistic effects on CCR5. 1145 72

An increase or accumulation in tissue inhibitor of matrix metalloproteinases-3 (TIMP-3) protein in Bruch's membrane with ageing in normal eyes, and in age related macular degeneration (AMD) has been previously demonstrated. The purpose of this study was to determine whether the expression of TIMP-3 mRNA increases with age, and to define any relationship between altered expression and Bruch's membrane thickness. Normal eyes were obtained from 30 donors (age range 15-90 years). Full-thickness 8 mm macular punches centred on the fovea were taken to allow removal of the chorioretinal complex, for subsequent nucleic acid extraction. Samples were normalized for RNA degradation using beta-actin reverse transcriptase-polymerase chain reaction (RT-PCR). A competitive RT-PCR was then used to allow measurement of TIMP-3 gene expression in each sample. The tissue adjacent to that used for nucleic acid extraction was processed histologically to allow determination of Bruch's membrane thickness. Bruch's membrane thickness was found to increase with age (P < 0.01), but TIMP-3 expression, as measured by competitive RT-PCR, was not significantly increased with age (P = 0.19). An inverse correlation was noted between TIMP-3 expression and Bruch's membrane thickness after controlling for age (P = 0.032). The results of this study suggest that TIMP-3 expression does not alter significantly with age. Therefore, accumulation of the TIMP-3 protein must occur by a mechanism other than increased expression. TIMP-3 protein levels may still prove to contribute to events associated with ageing in the macula, such as matrix remodelling in Bruch's membrane. Further studies are required to elucidate the precise interactions and turnover of the TIMP-3 protein, and resulting changes in the control of matrix metalloproteinase activity in the ageing macula.
 ...
PMID:Measurement of TIMP-3 expression and Bruch's membrane thickness in human macula. 1184 15

Issues, such as complexity, tolerability, and drug resistance and cross-resistance, limit the effectiveness of current antiretroviral regimens and make the continued development of newer agents important, despite the availability of 20 approved drugs for the treatment of HIV infection. Many new compounds are in development in existing classes: nucleoside and nucleotide analogue reverse transcriptase inhibitors (eg, D-d4FC and SPD754), non-nucleoside analogue reverse transcriptase inhibitors (eg, capravirine and TMC125), and protease inhibitors (eg, tipranavir and TMC114). In addition, newer classes of antiretroviral drugs, such as HIV entry inhibitors (eg, TNX-355, SCH 417690, UK-427,857, AMD 11070), that target the first step in the HIV life cycle are under development. Continued improvement in the treatment of HIV infection will result from the availability of convenient, well-tolerated, and affordable drugs with potent and durable antiretroviral activity.
 ...
PMID:New Antiretroviral Agents for the Treatment of HIV Infection. 1526 63

Current therapeutic intervention in HIV infection relies upon 20 different drugs. Despite the impressive efficacy shown by these drugs, we are confronted with an unexpected frequency of adverse effects, such as mitochondrial toxicity and lipodystrophy, and resistance, not only to individual drugs but to entire drug classes.Thus, there is now a great need for new antiretroviral drugs with reduced toxicity, increased activity against drug-resistant viruses and a greater capacity to reach tissue sanctuaries of the virus. Two different HIV molecules have been selected as targets of drug inhibition so far: reverse transcriptase and protease. Drugs that target the interactions between the HIV envelope and the cellular receptor complex are a 'new entry' into the scenario of HIV therapy and have recently raised great interest because of their activity against multidrug-resistant viruses. There are several compounds that are at different developmental stages in the pipeline to counter HIV entry, among them: (i) the attachment inhibitor dextrin-2-sulfate; (ii) the inhibitors of the glycoprotein (gp) 120/CD4 interaction PRO 542, TNX 355 and BMS 488043; (iii) the co-receptor inhibitors subdivided in those targeting CCR5 (SCH 417690 [SCH D], UK 427857 GW 873140, PRO 140, TAK 220, AMD 887) and those targeting CXCR4 (AMD 070, KRH 2731); and (iv) the fusion inhibitors enfuvirtide (T-20) and tifuvirtide (T-1249). The story of the first of these drugs, enfuvirtide, which has successfully completed phase III clinical trials, has been approved by the US FDA and by the European Medicines Agency, and is now commercially available worldwide, is an example of how the knowledge of basic molecular mechanisms can rapidly translate into the development of clinically effective molecules.
 ...
PMID:The appealing story of HIV entry inhibitors : from discovery of biological mechanisms to drug development. 1589 86

There are now exactly 20 anti-HIV drugs licenced (approved) for clinical use, and > 30 anti-HIV compounds under (pre)clinical development. The licensed anti-HIV drugs fall into five categories: nucleoside reverse transcriptase inhibitors (NRTIs: zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir and emtricitabine); nucleotide reverse transcriptase inhibitors (NtRTIs: tenofovir disoproxil fumarate); non-nucleoside reverse transcriptase inhibitors (NNRTIs: nevirapine, delavirdine and efavirenz); protease inhibitors (PIs: saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir, atazanavir and fosamprenavir); and fusion inhibitors (FIs: enfuvirtide). The compounds that are currently under clinical (Phase I, II or III) or preclinical investigation are either targeted at the same specific viral proteins as the licensed compounds (i.e., reverse transcriptase [NRTIs: PSI-5004, (-)-dOTC, DPC-817, elvucitabine, alovudine, MIV-210, amdoxovir, DOT; NNRTIs: thiocarboxanilide, UC-781, capravirine, dapivirine, etravirine, rilpivirine], protease [PIs: tipranavir, TMC-114]) or other specific viral proteins (i.e., gp120: cyanovirin N; attachment inhibitors: AIs, such as BMS-488043; integrase: L-870,812, PDPV-165; capsid proteins: PA-457, alpha-HCG); or cellular proteins (CD4 downmodulators: CADAs; CXCR4 antagonists: AMD-070, CS-3955; CCR5 antagonists: TAK-220, SCH-D, AK-602, UK-427857). Combination therapy is likely to remain the gold standard for the treatment of AIDS so as to maximise potency, minimise toxicity and diminish the risk for resistance development. Ideally, pill burden should be reduced to once-daily dosing so as to optimise the patient's compliance and reduce the treatment costs.
 ...
PMID:Emerging anti-HIV drugs. 1593 66

Issues, such as complexity, tolerability, and drug resistance and cross-resistance, limit the effectiveness of current antiretroviral regimens and make the continued development of newer agents important, despite the availability of 20 approved drugs for the treatment of HIV infection. Many new compounds are in development in existing classes: nucleoside and nucleotide analogue reverse transcriptase inhibitors (eg, D-d4FC and SPD754), non-nucleoside analogue reverse transcriptase inhibitors (eg, capravirine and TMC125), and protease inhibitors (eg, tipranavir and TMC114). In addition, newer classes of antiretroviral drugs, such as HIV entry inhibitors (eg, TNX-355, SCH 417690, UK-427,857, AMD 11070), that target the first step in the HIV life cycle are under development. Continued improvement in the treatment of HIV infection will result from the availability of convenient, well-tolerated, and affordable drugs with potent and durable antiretroviral activity.
 ...
PMID:New antiretroviral agents for the treatment of HIV infection. 1609 Dec 27

Current targets for antiretroviral therapy (ART) include the viral enzymes reverse transcriptase and protease. The use of a combination of inhibitors targeting these enzymes can reduce viral load for a prolonged period and delay disease progression. However, complications of ART, including the emergence of viruses resistant to current drugs, are driving the development of new antiretroviral agents targeting not only the reverse transcriptase and protease enzymes but novel targets as well. Indeed, enfuvirtide, an inhibitor targeting the viral envelope protein (Env) was recently approved for use in combination therapy in individuals not responding to current antiretroviral regimens. Emerging drug targets for ART include: (i) inhibitors that directly or indirectly target Env; (ii) the HIV enzyme integrase; and (iii) inhibitors of maturation that target the substrate of the protease enzyme. Env mediates entry of HIV into target cells via a multistep process that presents three distinct targets for inhibition by viral and cellular-specific agents. First, attachment of virions to the cell surface via nonspecific interactions and CD4 binding can be blocked by inhibitors that include cyanovirin-N, cyclotriazadisulfonamide analogues, PRO 2000, TNX 355 and PRO 542. In addition, BMS 806 can block CD4-induced conformational changes. Secondly, Env interactions with the co-receptor molecules can be targeted by CCR5 antagonists including SCH-D, maraviroc (UK 427857) and aplaviroc (GW 873140), and the CXCR4 antagonist AMD 070. Thirdly, fusion of viral and cellular membranes can be inhibited by peptides such as enfuvirtide and tifuvirtide (T 1249). The development of entry inhibitors has been rapid, with an increasing number entering clinical trials. Moreover, some entry inhibitors are also being evaluated as candidate microbicides to prevent mucosal transmission of HIV. The integrase enzyme facilitates the integration of viral DNA into the host cell genome. The uniqueness and specificity of this reaction makes integrase an attractive drug target. However, integrase inhibitors have been slow to reach clinical development, although recent contenders, including L 870810, show promise. Inhibitors that target viral maturation via a unique mode of action, such as PA 457, also have potential. In addition, recent advances in our understanding of cellular pathways involved in the life cycle of HIV have also identified novel targets that may have potential for future antiretroviral intervention, including interactions between the cellular proteins APOBEC3G and TSG101, and the viral proteins Vif and p6, respectively. In summary, a number of antiretroviral agents in development make HIV entry, integration and maturation emerging drug targets. A multifaceted approach to ART, using combinations of inhibitors that target different steps of the viral life cycle, has the best potential for long-term control of HIV infection. Furthermore, the development of microbicides targeting HIV holds promise for reducing HIV transmission events.
 ...
PMID:Emerging drug targets for antiretroviral therapy. 1611 75

Age-related macular degeneration is the leading cause of vision loss in elderly individuals, as well as a medical and socio-economic challenge. The treatment of dry age-related macular degeneration is based on vitamin supplementation. New treatment studies are focused on preventing the progression of degeneration and repopulating the atrophic macula. Recently, research on the treatment of neovascular age-related macular degeneration experienced a breakthrough with the advent of anti-vascular endothelial growth factor inhibitors. Nevertheless, despite the fact that ranibizumab, aflibercept, and bevacizumab are effective in reducing severe visual impairment, patients usually lose some vision over time. Therefore, the search for new therapies and diagnostic methods is fundamentally important. Current studies are focused on new anti-vascular endothelial growth factor drugs, nucleoside reverse transcriptase inhibitors, antibody against sphingosine-1-phosphate, anti-platelet-derived growth factor, gene therapy, and RNA interference. The results of ongoing clinical studies may improve the therapy of age-related macular degeneration.
 ...
PMID:Age-related macular degeneration: a review of current therapies and new treatments. 3278 36