Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.7 (DNA polymerase)
 17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 3.5 angstrom resolution electron density map of the HIV-1 reverse transcriptase heterodimer complexed with nevirapine, a drug with potential for treatment of AIDS, reveals an asymmetric dimer. The polymerase (pol) domain of the 66-kilodalton subunit has a large cleft analogous to that of the Klenow fragment of Escherichia coli DNA polymerase I. However, the 51-kilodalton subunit of identical sequence has no such cleft because the four subdomains of the pol domain occupy completely different relative positions. Two of the four pol subdomains appear to be structurally related to subdomains of the Klenow fragment, including one containing the catalytic site. The subdomain that appears likely to bind the template strand at the pol active site has a different structure in the two polymerases. Duplex A-form RNA-DNA hybrid can be model-built into the cleft that runs between the ribonuclease H and pol active sites. Nevirapine is almost completely buried in a pocket near but not overlapping with the pol active site. Residues whose mutation results in drug resistance have been approximately located.
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PMID:Crystal structure at 3.5 A resolution of HIV-1 reverse transcriptase complexed with an inhibitor. 137 3

In the search for 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives, we have found 6-benzyl-1-(ethoxymethyl)-5-isopropyl-uracil (MKC-442) to be a highly potent and selective inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). The IC50 value of MKC-442 for HIV-1 RT was 8 nM. MKC-442 did not inhibit HIV-1 RNase H, other RTs, or DNA polymerase alpha. Because its inhibitory pattern showed noncompetitive inhibition with regard to nucleotide substrates, its mode of action was considered to be allosteric inhibition. From the results of combination studies, MKC-442 was found to produce synergistic inhibition of HIV-1 RT with 3'-azido-2',3'-dideoxythymidine (AZT) 5'-triphosphate (AZT.TP). The dose of AZT.TP required for 50% inhibition was reduced to one tenth of control in the presence of a half dose of MKC-442. Although other allosteric inhibitors (Nevirapine, L-696,229, and R82,913) had the same specificity for enzyme inhibition, they did not show synergism with AZT.TP in the combination index and synergy plot analyses. Synergistic inhibition of HIV-1 replication by MKC-442 and AZT has also been observed in HIV-1-infected MT-4 cells. These results suggest that MKC-442 is a unique inhibitor of HIV-1 RT, and combination therapy with MKC-442 and AZT could be advantageous in the treatment of acquired immune deficiency syndrome.
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PMID:Selective and synergistic inhibition of human immunodeficiency virus type 1 reverse transcriptase by a non-nucleoside inhibitor, MKC-442. 769 70

Vertical transmission of HIV infection can take place in utero, during delivery and postnatally through breastfeeding, with about three-quarters of infections occurring around the time of delivery in non-breastfeeding populations. In Europe, in the absence of specific interventions, the vertical transmission rate was 15-20%. High maternal load is the major risk factor for both intra-uterine and intra-partum mother-to-child transmission. Prematurity is the most common adverse neonatal outcome associated with maternal HIV infection. Earlier diagnosis of paediatric HIV infection than previously available is now possible with virological tests, particularly HIV DNA polymerase chain reaction. An estimated one fifth of infected children will have been diagnosed with AIDS or have died by 12 months of age, rising to a third by 6 years of age. Surgical and therapeutic interventions are effective in reducing vertical transmission risk, in addition to the avoidance of breastfeeding. Caesarean section delivery before labour and before rupture of membranes approximately halves the risk of transmission, while prophylactic zidovudine therapy according to the ACTG076 regimen reduces transmission by up to two-thirds, transmission is reduced even further with both interventions. Trials of short-course zidovudine regimens show their effectiveness in reducing vertical transmission, in breastfeeding and non-breastfeeding populations. Nevirapine has been shown to be significantly more effective than short course zidovudine regimens in breastfeeding populations, but is still under evaluation in non-breastfeeding populations additionally receiving routine anti-retroviral prophylaxis. Reports of a small number of serious adverse events in uninfected children exposed in utero or neonatally to antiretroviral therapy need further investigation. Trials of vitamin A supplementation to reduce vertical transmission have had negative results, while the effectiveness of vaginal lavage and passive immune therapy in reducing vertical transmission remains uncertain.
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PMID:Epidemiology of HIV infection in the newborn. 1078 32