The replication of HIV-1 requires the integration of its cyclic DNA into host DNA by HIV-1 integrase （IN）, which includes two important reactions, 3＇-processing and strand transfer, both catalyzed by HIV-1 IN. Disr...The replication of HIV-1 requires the integration of its cyclic DNA into host DNA by HIV-1 integrase （IN）, which includes two important reactions, 3＇-processing and strand transfer, both catalyzed by HIV-1 IN. Disrupting either of the reactions will fulfill the purpose of inhibiting the replication of HIV-1. In this paper, pharmacophore modeling and molecular docking are employed to investigate the inhibition mechanism of the HIV-1 IN strand transfer inhibitors （INSTIs）. Based on the results, we suggest that the inhibition mechanism of INSTIs involves the inhibitor chelating the cofactors Mg2＋ and its forming hydrogen bonds with some crucial residues adjacent to the DDE active center.展开更多
Twenty novel furanone derivatives, based on the structure of raltegravir which was the first HIV-1 inte- grase（IN） inhibitor approved by the United States Food and Drug Administration（US FDA）, were designed, synth...Twenty novel furanone derivatives, based on the structure of raltegravir which was the first HIV-1 inte- grase（IN） inhibitor approved by the United States Food and Drug Administration（US FDA）, were designed, synthesized and characterized by ^1H NMR, IR and MS. The biological activities of these compounds against HIV-1 IN in vitro were evaluated. The assay results indicate that the replacement of pyrimidinone with furanone decreased the inhibitory activity of the compounds to HIV-1 IN. Compounds 3i, 3j and 3t show moderate inhibitory activity against HIV-1 IN and selectively inhibit the strand transfer reaction.展开更多
In this research, an unusually dimeric G-quadruplex of d（GGGTGGGTGGGTGGGT） （SI）, the potent nanomolar HIV-1 integrase inhibitor, was detected by nuclear magnetic resonance （NMR）. This result has been confirmed b...In this research, an unusually dimeric G-quadruplex of d（GGGTGGGTGGGTGGGT） （SI）, the potent nanomolar HIV-1 integrase inhibitor, was detected by nuclear magnetic resonance （NMR）. This result has been confirmed by electrospray ionization mass spectrometry （ESI-MS） and circular dichroism （CD）.展开更多
As one of the three viral encoded enzymes of HIV-1 infection, HIV-1 integrase has become an attractive drug target for the treatment. Diketoacid compounds （DKAs） are one kind of potent and selective inhibitors of HI...As one of the three viral encoded enzymes of HIV-1 infection, HIV-1 integrase has become an attractive drug target for the treatment. Diketoacid compounds （DKAs） are one kind of potent and selective inhibitors of HIV-1 IN. In the present work, two three-dimensional QSAR techniques （CoMFA and CoMSIA） were employed to correlate the molecular structure with the activity of inhibiting the strand transfer for 147 DKAs. The all-oritation search （AOS） and all-placement search （APS） were used to optimize the CoMFA model. The diketo and keto-enol tautomers of DKAs were also used to establish the CoMFA models. The results indicated that the enol was the dominant conformation in the HIV-1 IN and DKAs complexes. It can provide a new method and reference to identify the bioactive conformation of drugs by using QSAR analysis. The best CoMSIA model, with five fields combined, implied that the hydrophobic field is very important as well as the steric and electrostatic fields. All models indicated favorable internal validation. A comparative analysis with the three models demonstrated that the CoMFA model seems to be more predictive. The contour maps could afford steric, electrostatic, hydrophobic and H-bond information about the interaction of ligand-receptor complex visually. The models would give some useful guidelines for designing novel and potent HIV-1 integrase inhibitors.展开更多
Lipinski’s “Rule of Five” was introduced for predicting oral bioavailability to describe drug-like molecules. For the purpose of this research the rules were used to separate potential inhibitors of HIV-1 integrase...Lipinski’s “Rule of Five” was introduced for predicting oral bioavailability to describe drug-like molecules. For the purpose of this research the rules were used to separate potential inhibitors of HIV-1 integrase (1BIS.pdb) into two groups: drug-like and nondrug-like. If one of Lipinski’s “Rule of Five” was not followed the potential inhibitor was classified as nondrug-like. Thirty molecules were identified from the literature, twenty-four drug-like and six nondrug-like, that were docked into the active site of 1BIS.pdb (considered the non-mutated protein) and two mutant models, Y143R and N155H. These are two of the mutations that have led to increased resistance to HIV-1 integrase drugs such as raltegravir and elvitegravir. The computational software, ICM-Pro (Molsoft L.L.C.), was used to determine the estimated binding energy (EBE) of the drug/protein complex. It was found that the nondrug-like molecules generally had a more negative EBE, that is, tighter binding with 1BIS. pdb, though there were several exceptions in the drug-like group. With the protein mutant model Y143R, the majority of drug-like (58%) and nondrug-like molecules (67%) had tighter binding. However, for the mutant model N155H, there was the same percent (46%) of drug-like molecules with tighter binding with the mutant model as with 1BIS.pdb. The drug-like molecules were used when there was a ≥1 kcal/mole difference between 1BIS.pdb and either of the two mutant models to suggest a pharmacophore with structural characteristics for an HIV-1 integrase inhibitor.展开更多
The title compound （C50H.44010） was synthesized and structurally determined by single-crystal X-ray diffraction method. It crystallizes in monoclinic, space group P21/c with a = 16.713（4）, b --- 13.189（3）, c = 1...The title compound （C50H.44010） was synthesized and structurally determined by single-crystal X-ray diffraction method. It crystallizes in monoclinic, space group P21/c with a = 16.713（4）, b --- 13.189（3）, c = 19.434（5） A, β = 104.411（4）°, Mr = 804.85, Dc = 1.288 g/cm3, V = 4149.2（17） A3, Z = 4, F（000） = 1696, #（MoKa） = 0.089 mm-1T = 296（2） K, 7279 independent reflections with 3172 observed ones （I 〉 2δ（/））, R = 0.0520 and wR = 0.1203 with GOF = 0.928 （R = 0.1464 and wR = 0.1657 for all data）. The calixarene moiety maintains the symmetric cone conformation through intramolecular O-H…O hydrogen bonds. Preliminary bioassays indicated that the title compound has a potent inhibitory activity against the strand transfer process of HIV-1 integrase.展开更多
Despite enormous efforts to achieve the goal of eliminating mother-to-child transmission of HIV-1, it remains a major challenge for many countries in sub-Saharan Africa, particularly Mali. Our objective is to assess c...Despite enormous efforts to achieve the goal of eliminating mother-to-child transmission of HIV-1, it remains a major challenge for many countries in sub-Saharan Africa, particularly Mali. Our objective is to assess changes in the rate of mother-to-child transmission of HIV-1. We conducted a cross-sectional study between January 1, 2009 to December 31, 2018 (10 years) of early diagnosis activity in newborns and children born to HIV-1-positive mothers at the National Institute for Public Health (INSP). The samples came from health and referral centers in mali. All samples were received at the Laboratory of Molecular Biology at the INSP. Proviral DNA extraction was performed from a blood spot sample with a Roche DNA kit, Cobas AmpliPrep/Cobas TaqMan HIV-1 qualitative Test, V2.0 (Roche Molecular System, Inc, USA) following the company procedures. Molecular diagnosis was performed using the same kits using an algorithm of three identical PCRs. The Epi Info version 7 software was used for data analysis with a significance threshold of 5%. A total of 10,714 samples of infants and children born to HIV-positive mothers were analyzed by PCR. Ninety-six percent of mothers were on ARV prophylaxis (AZT 3TC NVP and AZT NVP) and 60% of newborns received the same ARV prophylaxis. Of these children, 956 tested positive with an overall transmission rate of 8.92%, varying between 7.27% in 2009 and 08.01% in 2018. This rate was relatively low among children receiving prophylaxis at 2.04% and remained high for children who received breastfeeding at 5.62%. However, the transmission rate remains low for those who have benefited from mixed and artificial breastfeeding at 1.58% and 1.27% respectively. A significant proportion of children remained infected by their mothers during pregnancy, childbirth or breastfeeding. This study shows the importance of early diagnosis of HIV in children using molecular technology.展开更多
The emergence of antiretroviral resistance mutations represents a major threat to the achievement of national and global goals for the elimination of HIV-1 infection. The global strategy in 2019 in Cte d'Ivoire is...The emergence of antiretroviral resistance mutations represents a major threat to the achievement of national and global goals for the elimination of HIV-1 infection. The global strategy in 2019 in Cte d'Ivoire is a new national policy for the management of people living with HIV with the administration of dolutegravir (DTG)-based fixed-dose combination. The aim of our study was to evaluate HIV-1 resistance to antiretrovirals (ARVs) in infected adult subjects in Cte d’Ivoire in the context of a systematic switch to a DTG-based combination. Between February 2022 and October 2023, a cross-sectional survey with random sampling was conducted in 06 services caring for people living with HIV. A total of 139 participants were included in the study. Adults with a viral load ≥ 1000 copies/mL were tested for HIV-1 ARV resistance mutations. Molecular analyses were performed using protocol of ANRS-MIE (National Agency for Research on AIDS and emerging infectious diseases). The interpretation is performed by HIVGRAD (https://www.hiv-grade.de/cms/grade/). The frequencies of HIV-1 resistance to non-nucleotide reverse transcriptase inhibitors (NNRTIs), nucleotide reverse transcriptase inhibitors (NRTIs), integrase inhibitors (IINTs) and protease inhibitors (PIs) were 82%, 73%, 19% and 11% respectively. The main mutations observed in the different classes were K103N (45%), M184V (64%), E157Q (19%) and L10V/M46I/A71V/I54V (6%) respectively. This study reveals the emergence of resistance to DTG-based fixed-dose combinations, favored by high rates of resistance to NRTIs and NNRTIs. This finding underlines the need for enhanced viral load monitoring and HIV-1 genotyping tests to guide the choice of NRTIs for combination therapy. In addition, monitoring for mutations to second-generation NRTIs is essential, given the scale-up of DTG-based regimens currently underway in Cte d’Ivoire.展开更多
Introduction: HIV, the human immunodeficiency virus, is the etiological agent of acquired immunodeficiency syndrome (AIDS). The aim of this study was to assess the evolution of the viral load in patients under treatme...Introduction: HIV, the human immunodeficiency virus, is the etiological agent of acquired immunodeficiency syndrome (AIDS). The aim of this study was to assess the evolution of the viral load in patients under treatment. Methodology: This was a study carried out from July 2017 to June 2022 at the Point G University Hospital laboratory. The determination of the viral load of patients was carried out by PCR on the ABOTT M2000sp/rt platform. Results: A total of 129 patients infected with HIV-1, aged 19 to 72 years with a mean age of 40.05 years ± 10.71;all on antiretroviral chemotherapy. The female gender predominated among our patients. The most common treatment regimen was 2INTI + 1INNTI with 72.9% followed by 2INTI + 1INI with 13.2%. As for the combinations of molecules, the combination TDF + 3TC + EFV and TDF + 3TC + DTG predominated, respectively 65.1% and 13.2%. 89.9% of our patients had undetectable viremia after 12 months of treatment (p < 0.005) with an average viral load which had evolved from 681315.65 copies/ml ± 1616908.484 to M0 at 5742.36 copies /ml ± 35756.883 at M12 (p Conclusion: Generally speaking, antiretroviral treatment had contributed to controlling viral loads, however the therapeutic combination TDF + 3TC + DTG had made it possible to obtain more patients with undetectable viremia instead.展开更多
基金supported by the National Natural Science Foundation of China (No. 30472166)the Tianjin Commission of Science and Technology (06YFGZSH07000)
文摘The replication of HIV-1 requires the integration of its cyclic DNA into host DNA by HIV-1 integrase （IN）, which includes two important reactions, 3＇-processing and strand transfer, both catalyzed by HIV-1 IN. Disrupting either of the reactions will fulfill the purpose of inhibiting the replication of HIV-1. In this paper, pharmacophore modeling and molecular docking are employed to investigate the inhibition mechanism of the HIV-1 IN strand transfer inhibitors （INSTIs）. Based on the results, we suggest that the inhibition mechanism of INSTIs involves the inhibitor chelating the cofactors Mg2＋ and its forming hydrogen bonds with some crucial residues adjacent to the DDE active center.
基金Supported by the National Natural Science Foundation of China(No.20872082)the Natural Science Foundation of Shandong Province,China(No.Y2007C060)
文摘Twenty novel furanone derivatives, based on the structure of raltegravir which was the first HIV-1 inte- grase（IN） inhibitor approved by the United States Food and Drug Administration（US FDA）, were designed, synthesized and characterized by ^1H NMR, IR and MS. The biological activities of these compounds against HIV-1 IN in vitro were evaluated. The assay results indicate that the replacement of pyrimidinone with furanone decreased the inhibitory activity of the compounds to HIV-1 IN. Compounds 3i, 3j and 3t show moderate inhibitory activity against HIV-1 IN and selectively inhibit the strand transfer reaction.
基金the National Natural Science Foundation of China(No.20472009)the Research Fund for the Doctoral Program of Higher Education.
文摘In this research, an unusually dimeric G-quadruplex of d（GGGTGGGTGGGTGGGT） （SI）, the potent nanomolar HIV-1 integrase inhibitor, was detected by nuclear magnetic resonance （NMR）. This result has been confirmed by electrospray ionization mass spectrometry （ESI-MS） and circular dichroism （CD）.
基金supported by the Natural Science Foundation of Zhejiang Province (Y. 4090578)
文摘As one of the three viral encoded enzymes of HIV-1 infection, HIV-1 integrase has become an attractive drug target for the treatment. Diketoacid compounds （DKAs） are one kind of potent and selective inhibitors of HIV-1 IN. In the present work, two three-dimensional QSAR techniques （CoMFA and CoMSIA） were employed to correlate the molecular structure with the activity of inhibiting the strand transfer for 147 DKAs. The all-oritation search （AOS） and all-placement search （APS） were used to optimize the CoMFA model. The diketo and keto-enol tautomers of DKAs were also used to establish the CoMFA models. The results indicated that the enol was the dominant conformation in the HIV-1 IN and DKAs complexes. It can provide a new method and reference to identify the bioactive conformation of drugs by using QSAR analysis. The best CoMSIA model, with five fields combined, implied that the hydrophobic field is very important as well as the steric and electrostatic fields. All models indicated favorable internal validation. A comparative analysis with the three models demonstrated that the CoMFA model seems to be more predictive. The contour maps could afford steric, electrostatic, hydrophobic and H-bond information about the interaction of ligand-receptor complex visually. The models would give some useful guidelines for designing novel and potent HIV-1 integrase inhibitors.
文摘Lipinski’s “Rule of Five” was introduced for predicting oral bioavailability to describe drug-like molecules. For the purpose of this research the rules were used to separate potential inhibitors of HIV-1 integrase (1BIS.pdb) into two groups: drug-like and nondrug-like. If one of Lipinski’s “Rule of Five” was not followed the potential inhibitor was classified as nondrug-like. Thirty molecules were identified from the literature, twenty-four drug-like and six nondrug-like, that were docked into the active site of 1BIS.pdb (considered the non-mutated protein) and two mutant models, Y143R and N155H. These are two of the mutations that have led to increased resistance to HIV-1 integrase drugs such as raltegravir and elvitegravir. The computational software, ICM-Pro (Molsoft L.L.C.), was used to determine the estimated binding energy (EBE) of the drug/protein complex. It was found that the nondrug-like molecules generally had a more negative EBE, that is, tighter binding with 1BIS. pdb, though there were several exceptions in the drug-like group. With the protein mutant model Y143R, the majority of drug-like (58%) and nondrug-like molecules (67%) had tighter binding. However, for the mutant model N155H, there was the same percent (46%) of drug-like molecules with tighter binding with the mutant model as with 1BIS.pdb. The drug-like molecules were used when there was a ≥1 kcal/mole difference between 1BIS.pdb and either of the two mutant models to suggest a pharmacophore with structural characteristics for an HIV-1 integrase inhibitor.
基金supported by the National Natural Science Foundation of China(No.21102003)National Students'Innovation and Entrepreneurship Training Program(No.201210361094)Scientific Research Foundation for the Introduction of Talent and Young Teachers Scientific Research Foundation of Anhui University of Science&Technology(11214,2012QNY27)
文摘The title compound （C50H.44010） was synthesized and structurally determined by single-crystal X-ray diffraction method. It crystallizes in monoclinic, space group P21/c with a = 16.713（4）, b --- 13.189（3）, c = 19.434（5） A, β = 104.411（4）°, Mr = 804.85, Dc = 1.288 g/cm3, V = 4149.2（17） A3, Z = 4, F（000） = 1696, #（MoKa） = 0.089 mm-1T = 296（2） K, 7279 independent reflections with 3172 observed ones （I 〉 2δ（/））, R = 0.0520 and wR = 0.1203 with GOF = 0.928 （R = 0.1464 and wR = 0.1657 for all data）. The calixarene moiety maintains the symmetric cone conformation through intramolecular O-H…O hydrogen bonds. Preliminary bioassays indicated that the title compound has a potent inhibitory activity against the strand transfer process of HIV-1 integrase.
文摘Despite enormous efforts to achieve the goal of eliminating mother-to-child transmission of HIV-1, it remains a major challenge for many countries in sub-Saharan Africa, particularly Mali. Our objective is to assess changes in the rate of mother-to-child transmission of HIV-1. We conducted a cross-sectional study between January 1, 2009 to December 31, 2018 (10 years) of early diagnosis activity in newborns and children born to HIV-1-positive mothers at the National Institute for Public Health (INSP). The samples came from health and referral centers in mali. All samples were received at the Laboratory of Molecular Biology at the INSP. Proviral DNA extraction was performed from a blood spot sample with a Roche DNA kit, Cobas AmpliPrep/Cobas TaqMan HIV-1 qualitative Test, V2.0 (Roche Molecular System, Inc, USA) following the company procedures. Molecular diagnosis was performed using the same kits using an algorithm of three identical PCRs. The Epi Info version 7 software was used for data analysis with a significance threshold of 5%. A total of 10,714 samples of infants and children born to HIV-positive mothers were analyzed by PCR. Ninety-six percent of mothers were on ARV prophylaxis (AZT 3TC NVP and AZT NVP) and 60% of newborns received the same ARV prophylaxis. Of these children, 956 tested positive with an overall transmission rate of 8.92%, varying between 7.27% in 2009 and 08.01% in 2018. This rate was relatively low among children receiving prophylaxis at 2.04% and remained high for children who received breastfeeding at 5.62%. However, the transmission rate remains low for those who have benefited from mixed and artificial breastfeeding at 1.58% and 1.27% respectively. A significant proportion of children remained infected by their mothers during pregnancy, childbirth or breastfeeding. This study shows the importance of early diagnosis of HIV in children using molecular technology.
文摘The emergence of antiretroviral resistance mutations represents a major threat to the achievement of national and global goals for the elimination of HIV-1 infection. The global strategy in 2019 in Cte d'Ivoire is a new national policy for the management of people living with HIV with the administration of dolutegravir (DTG)-based fixed-dose combination. The aim of our study was to evaluate HIV-1 resistance to antiretrovirals (ARVs) in infected adult subjects in Cte d’Ivoire in the context of a systematic switch to a DTG-based combination. Between February 2022 and October 2023, a cross-sectional survey with random sampling was conducted in 06 services caring for people living with HIV. A total of 139 participants were included in the study. Adults with a viral load ≥ 1000 copies/mL were tested for HIV-1 ARV resistance mutations. Molecular analyses were performed using protocol of ANRS-MIE (National Agency for Research on AIDS and emerging infectious diseases). The interpretation is performed by HIVGRAD (https://www.hiv-grade.de/cms/grade/). The frequencies of HIV-1 resistance to non-nucleotide reverse transcriptase inhibitors (NNRTIs), nucleotide reverse transcriptase inhibitors (NRTIs), integrase inhibitors (IINTs) and protease inhibitors (PIs) were 82%, 73%, 19% and 11% respectively. The main mutations observed in the different classes were K103N (45%), M184V (64%), E157Q (19%) and L10V/M46I/A71V/I54V (6%) respectively. This study reveals the emergence of resistance to DTG-based fixed-dose combinations, favored by high rates of resistance to NRTIs and NNRTIs. This finding underlines the need for enhanced viral load monitoring and HIV-1 genotyping tests to guide the choice of NRTIs for combination therapy. In addition, monitoring for mutations to second-generation NRTIs is essential, given the scale-up of DTG-based regimens currently underway in Cte d’Ivoire.
文摘Introduction: HIV, the human immunodeficiency virus, is the etiological agent of acquired immunodeficiency syndrome (AIDS). The aim of this study was to assess the evolution of the viral load in patients under treatment. Methodology: This was a study carried out from July 2017 to June 2022 at the Point G University Hospital laboratory. The determination of the viral load of patients was carried out by PCR on the ABOTT M2000sp/rt platform. Results: A total of 129 patients infected with HIV-1, aged 19 to 72 years with a mean age of 40.05 years ± 10.71;all on antiretroviral chemotherapy. The female gender predominated among our patients. The most common treatment regimen was 2INTI + 1INNTI with 72.9% followed by 2INTI + 1INI with 13.2%. As for the combinations of molecules, the combination TDF + 3TC + EFV and TDF + 3TC + DTG predominated, respectively 65.1% and 13.2%. 89.9% of our patients had undetectable viremia after 12 months of treatment (p < 0.005) with an average viral load which had evolved from 681315.65 copies/ml ± 1616908.484 to M0 at 5742.36 copies /ml ± 35756.883 at M12 (p Conclusion: Generally speaking, antiretroviral treatment had contributed to controlling viral loads, however the therapeutic combination TDF + 3TC + DTG had made it possible to obtain more patients with undetectable viremia instead.
