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1.
Bioorg Chem ; : 105494, 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34836643

RESUMO

Both HIV and DENV are serious threats to human life, health and social economy today. So far, no vaccine for either HIV or DENV has been developed successfully. The research on anti-HIV or DENV drugs is still of great significance. In this study we developed a series of novel 2-Aryl-1H-pyrazole-S-DABOs with C6-strucutral optimizations as potent NNRTIs, among which, 8 compounds had low cytotoxicity and EC50 values in the range of 0.0508 âˆ¼ 0.0966 µM, and their selectivity index was SI > 1415 âˆ¼ 3940. In particular, two compounds 4a and 4b were identified to have good inhibitory effects on DENV of four serotypes. The EC50 of compound 4a and 4b against DENV-II (13.2 µM and 9.23 µM, respectively) were better than that of the positive control ribavirin (EC50 = 40.78 µM). In addition, the effect of C-6 substituents on the anti-HIV or anti-DENV activity of these compounds was also discussed.

2.
Nat Prod Res ; : 1-7, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34738856

RESUMO

A pair of new oxindole alkaloids, named macrophyllines C (1) and D (2), together with two known oxindole alkaloids isorhynchophylline (3) and corynoxine (4) were isolated from Uncaria macrophylla. Their structures were elucidated based on detailed spectroscopic analysis and by comparison with literature data. In addition, all the isolates were tested for their anti-HIV activities and cytotoxicities in C8166 cells and compounds 2-4 showed weak anti-HIV activities with EC50 values of 11.31 ± 3.29 µM, 18.77 ± 6.14 µM and 30.02 ± 3.73 µM, respectively.

3.
Virus Res ; 306: 198593, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34637814

RESUMO

Zika virus (ZIKV) is a typical mosquito-borne flavivirus known to cause severe fetal microcephaly and adult Guillain-Barré syndrome. Currently, there are no specific drugs or licensed vaccines available for ZIKV infection, and further research is required to identify host cell proteins involved in the virus's life cycle. Viruses are known to use host cell membrane skeletal proteins, such as actin and spectrin, to complete cell entry, transportation, and release. Here, based on immunoprecipitation, the Axl and ZIKV envelope (E) protein were shown to interact with the cell membrane skeleton protein 4.1R. Furthermore, deletion of 4.1R significantly reduced virus titer and viral protein synthesis. Our study showed that 4.1R is an important host cell protein during ZIKV infection and may be involved in the process of viral entry into host cells.

4.
Bioorg Chem ; 116: 105303, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34464815

RESUMO

Eucalyptus is a large genus of the Myrtaceae family with high value in various fields of industry. Recently, attention has been focused on the functional properties of Eucalyptus extracts. These extracts have been traditionally used to combat various infectious diseases, and volatile oils are usually considered to play a major role. But the positive effects of non-volatile acylphloroglucinols, a class of specialized metabolites with relatively high content in Eucalyptus, should not be neglected. Herein, non-volatile acylphloroglucinols from leaves of Eucalyptus robusta were evaluated for their abilities to inhibit Zika virus (ZIKV) which is associated with severe neurological damage and complications. The results showed eucalyprobusone G, a new symmetrical acylphloroglucinol dimer, possessed the significant ability to inhibit ZIKV without inducing cytotoxicity. The EC50 values of eucalyprobusone G against the African lineage (MR766) and Asian lineage (SZ-WIV01) of ZIKV were 0.43 ± 0.08 and 10.10 ± 3.84 µM which were 110 times and 5.8 times better than those of the reference compound ribavirin, respectively. Further action mode research showed that eucalyprobusone G impairs the viral binding and RdRp activity of NS5. The results broaden the functional properties of Eucalyptus robusta and indicate acylphloroglucinol dimers could be developed as anti-ZIKV agents.

5.
Nat Commun ; 12(1): 2257, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33859198

RESUMO

Naturally abundant quinones are important molecules, which play essential roles in various biological processes due to their reduction potential. In contrast to their universality, the investigation of reactions between quinones and proteins remains sparse. Herein, we report the development of a convenient strategy to protein modification via a biomimetic quinone-mediated oxidation at the N-terminus. By exploiting unique reactivity of an ortho-quinone reagent, the α-amine of protein N-terminus is oxidized to generate aldo or keto handle for orthogonal conjugation. The applications have been demonstrated using a range of proteins, including myoglobin, ubiquitin and small ubiquitin-related modifier 2 (SUMO2). The effect of this method is further highlighted via the preparation of a series of 17 macrophage inflammatory protein 1ß (MIP-1ß) analogs, followed by preliminary anti-HIV activity and cell viability assays, respectively. This method offers an efficient and complementary approach to existing strategies for N-terminal modification of proteins.


Assuntos
Antivirais/farmacologia , Materiais Biomiméticos/química , Biomimética/métodos , Quimiocina CCL4/farmacologia , Infecções por HIV/tratamento farmacológico , Aminas/química , Antivirais/química , Linhagem Celular Tumoral , Quimiocina CCL4/química , Quimiocina CCL4/genética , Quimiocina CCL4/isolamento & purificação , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Humanos , Mioglobina/química , Oxirredução , Processamento de Proteína Pós-Traducional , Quinonas/química , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/química , Ubiquitina/química , Replicação Viral/efeitos dos fármacos
7.
Bioorg Chem ; 102: 104041, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32683184

RESUMO

In order to discover and develop the new HIV-1 NNRTIs, a series of 5-alkyl-6-(benzo[d][1,3]dioxol-5-ylalkyl)-2-mercaptopyrimidin-4(3H)-ones was synthesized and screened for their in vitro cytotoxicity against HIV-1. Most of the compounds we synthetized showed high activity against wild-type HIV-1 strain (IIIB) while IC50 values are in the range of 0.06-12.95 µM. Among them, the most active HIV-1 inhibitor was compound 6-(benzo[d][1,3]dioxol-5-ylmethyl)-5-ethyl-2-((2-(4-hydroxyphenyl)-2-oxoethyl)thio)pyrimidin-4(3H)-one (5b), which exhibited similar HIV-1 inhibitory potency (IC50 = 0.06 µM, CC50 = 96.23 µM) compared with nevirapine (IC50 = 0.04 µM, CC50 >200 µM) and most of compounds exhibited submicromolar IC50 values indicating they were specific RT inhibitors. The compounds 5b, 6-(benzo[d] [1,3]dioxol-5-yl)-5-ethyl-2-((2-(4-hydroxyphenyl)-2-oxoethyl)thio)pyrimidin-4(3H)-one (5c) and 4-(2-((4-(benzo[d][1,3]dioxol-5-ylmethyl)-5-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)thio)acetyl)phenylbenzo[d][1,3]dioxole-5-carboxylate (5r) were selected for further study. It was found that all of them had little toxicity to peripheral blood mononuclear cell (PBMC), and had a good inhibitory effect on the replication of HIV-1 protease inhibitor resistant strains, fusion inhibitor resistant strains and nucleosides reverse transcriptase inhibitor resistant strains, as well as on clinical isolates. Besides, compound 5b and 5c showed inhibition of HIV-1 RT RNA-dependent DNA polymerization activity and DNA-dependent DNA polymerization activity, while compound 5r only showed inhibition of HIV DNA-dependent DNA polymerization activity, which was different from classical reverse transcriptase inhibitors. Our study which offered the preliminary structure-activity relationships and modeling studies of these new compounds has provided the valuable avenues for future molecular optimization.


Assuntos
Fármacos Anti-HIV/uso terapêutico , HIV-1/efeitos dos fármacos , Pirimidinonas/química , Inibidores da Transcriptase Reversa/uso terapêutico , Fármacos Anti-HIV/farmacologia , Desenho de Fármacos , Humanos , Modelos Moleculares , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade
8.
Int J Antimicrob Agents ; 55(4): 105926, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32092396

RESUMO

Antiretroviral therapy (ART) can effectively suppress replication of human immunodeficiency virus type 1 (HIV-1) and limit disease progression. However, ART is unable to eradicate the virus, and the requirement for lifelong treatment may have side effects and may lead to the development of resistance. New approaches to prevent and treat HIV-1 infection should therefore be developed. HIV-1 capsid (CA) protein is an unexploited but attractive target for antiviral drug development. The hydrophobic cavity of the C-terminal domain of CA (CA CTD) has been validated as a potential target for antiviral drugs. Binding of compounds to this conserved non-polar groove in CA CTD allosterically disrupts the CA assembly. This study screened 2080 natural products to identify potential antiviral agents for further development to combat HIV-1 infection. From the primary screen at a fixed concentration of 50 µM, 16 compounds were found to be effective against this target. Six compounds observed in the primary screen were confirmed in dose-response experiments, and were tested against HIV-1-induced cytopathic effects. Two compounds were found to inhibit HIV-1 replication, and the most active compound - rubranol - inhibited viral replication at a moderate micromolar concentration (EC50 = 15.85 µM). The binding modes of rubranol and hirsutanonol to CA CTD were analysed by molecular docking, providing insight for the design of drugs targeting HIV-1 CA. This study reports, for the first time, identification of natural products that showed potential as anti-HIV-1 agents by targeting the conserved hydrophobic cavity of HIV-1 CA CTD.


Assuntos
Fármacos Anti-HIV/farmacologia , Produtos Biológicos/farmacologia , Proteínas do Capsídeo/antagonistas & inibidores , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Capsídeo/efeitos dos fármacos , Proteínas do Capsídeo/efeitos dos fármacos , Linhagem Celular , Ácidos Cumáricos/farmacologia , Diarileptanoides/farmacologia , Dissacarídeos/farmacologia , Descoberta de Drogas/métodos , Glucosídeos/farmacologia , Humanos , Simulação de Acoplamento Molecular , Fenóis/farmacologia , Montagem de Vírus/efeitos dos fármacos , Xantonas/farmacologia
9.
J Nat Prod ; 82(7): 1813-1819, 2019 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-31310115

RESUMO

Eight new sulfur-bridged pyranonaphthoquinone (PNQ) dimers, naquihexcins C-J (1-8), a new PNQ monomer, naquihexcin K (10), and three known analogues (9, 11, and 12) were isolated from Streptomyces sp. KIB3133. The new structures were elucidated by interpretation of spectroscopic data. Dimer 4 was synthesized via a cascade SN2 reactions between two monomers and sodium sulfide, an approach motivated by the proposed biosynthetic pathway of dimeric pyranonaphthoquinones. Naquihexcin E (3) exhibited moderate HIV-1 inhibitory activity. Naquihexcins C (1), E (3), and I (7) showed inhibitory effects against two tumor cell lines (HL-60 and MCF-7) with IC50 values ranging from 1.4 to 16.1 µM.


Assuntos
Fármacos Anti-HIV/farmacologia , Antineoplásicos/farmacologia , Naftoquinonas/química , Piranos/química , Microbiologia do Solo , Streptomyces/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular Tumoral , Dimerização , Ensaios de Seleção de Medicamentos Antitumorais , HIV-1/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Naftoquinonas/farmacologia
10.
Antiviral Res ; 169: 104544, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31254557

RESUMO

Due to its multifaceted essential roles in virus replication and extreme genetic fragility, the human immunodeficiency virus type 1 (HIV-1) capsid (CA) protein is a valued therapeutic target. However, CA is as yet unexploited clinically, as there are no antiviral agents that target it currently on the market. To facilitate the identification of potential HIV-1 CA inhibitors, we established a homogeneous time-resolved fluorescence (HTRF) assay to screen for small molecules that target a biologically active and specific binding pocket in the C-terminal domain of HIV-1 CA (CA CTD). The assay, which is based on competition of small molecules for the binding of a known CA inhibitor (CAI) to the CA CTD, exhibited a signal-to-background ratio (S/B) > 10 and a Z' value > 0.9. In a pilot screen of three kinase inhibitor libraries containing 464 compounds, we identified one compound, TX-1918, as a low micromolecular inhibitor of the HIV-1 CA CTD-CAI interaction (IC50 = 3.81 µM) that also inhibited viral replication at moderate micromolar concentration (EC50 = 15.16 µM) and inhibited CA assembly in vitro. Based on the structure of TX-1918, an additional compound with an antiviral EC50 of 6.57 µM and cellular cytotoxicity CC50 of 102.55 µM was obtained from a compound similarity search. Thus, the HTRF-based assay has properties that are suitable for screening large compound libraries to identify novel anti-HIV-1 inhibitors targeting the CA CTD.


Assuntos
Ligação Competitiva , Proteínas do Capsídeo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Fluorescência , HIV-1/efeitos dos fármacos , Ensaios de Triagem em Larga Escala/métodos , Montagem de Vírus/efeitos dos fármacos , Capsídeo/efeitos dos fármacos , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/metabolismo , Linhagem Celular , Liberação Controlada de Fármacos , Proteínas Recombinantes , Linfócitos T , Replicação Viral/efeitos dos fármacos
11.
J Med Chem ; 61(21): 9621-9636, 2018 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-30234300

RESUMO

CC-chemokine receptor 5 (CCR5) is an attractive target for preventing the entry of human immunodeficiency virus 1 (HIV-1) into human host cells. Maraviroc is the only CCR5 antagonist, and it was marketed in 2007. To overcome the shortcomings of maraviroc, structure-based drug design was performed to minimize CYP450 inhibition and to enhance anti-HIV potency and bioavailability. Thirty-four novel 1-heteroaryl-1,3-propanediamine derivatives (1-34) were synthesized, displaying CCR5-antagonist activities in the 2.3-296.4 nM range. Among these, compounds 21 and 34 were the most potent CCR5 antagonists, with excellent in vitro anti-HIV-1 activity, low cytotoxicity, and an acceptable pharmacokinetic profile. Furthermore, the X-ray crystal structures of compounds 21 and 34 bound to CCR5 were determined at 2.8 Å resolution. Compound 34 exhibited no CYP450-inhibition activity at 25 µM, which overcomes the potential drug-drug interaction of maraviroc. Compound 34 represents a promising drug candidate for HIV-infection treatment.


Assuntos
Antagonistas dos Receptores CCR5/química , Antagonistas dos Receptores CCR5/farmacologia , Diaminas/química , Diaminas/farmacologia , Desenho de Fármacos , Receptores CCR5/metabolismo , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/toxicidade , Antagonistas dos Receptores CCR5/toxicidade , Linhagem Celular , Diaminas/toxicidade , Humanos , Modelos Moleculares , Conformação Proteica , Receptores CCR5/química
12.
Sci Rep ; 8(1): 2574, 2018 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-29416083

RESUMO

In a previous study the small molecule SJP-L-5 that inhibits HIV replication, has been shown to block uncoating of the viral capsid. Continued study showed that SJP-L-5 might hinder HIV capsid uncoating by blocking the completion of reverse transcription. However, to date, the mechanism has not been fully elucidated. Here, the effects of SJP-L-5 for reverse transcription were explored via quantitative PCR, DIG-labelled ELISA, fluorescent resonance energy transfer, and Southern blot assays. We also analyzed the resistance profile of this compound against reverse transcriptase. Our results show that SJP-L-5 preferentially inhibits PPT primed plus-strand DNA synthesis (EC50 = 13.4 ± 3.0 µM) over RNA primed minus-strand DNA synthesis (EC50 > 3,646 µM), resulting in formation of five segmented plus-strand DNA and loss of HIV DNA flap, suggesting failure of both nuclear import and integration. Moreover, resistance study evidenced that SJP-L-5 requires the amino acid residues Val108 and Tyr181 to exert an inhibitory effect. These results indicate SJP-L-5 as a new non-nucleoside reverse transcriptase inhibitor that inhibits HIV-1 polypurine tract primed plus-strand DNA synthesis, initiating HIV-1 down-stream plus-strand DNA synthesis at multiple sites under drug pressure.


Assuntos
Compostos de Bifenilo/farmacologia , Replicação do DNA/efeitos dos fármacos , DNA Viral/efeitos dos fármacos , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Replicação Viral/efeitos dos fármacos , Compostos de Bifenilo/química , Células Cultivadas , DNA Viral/genética , HIV-1/genética , HIV-1/fisiologia , Humanos , Inibidores da Transcriptase Reversa/química , Transcrição Genética/efeitos dos fármacos
13.
Med Chem ; 14(3): 249-252, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28969577

RESUMO

BACKGROUND: The human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) has always been a global health threat and leading cause of deaths. However, due to the emergence of drug-resistant HIV, an inevitable consequence of increasing use of antiretroviral drugs posed a major threat to antiretroviral therapy success. OBJECTIVE: The discovery of anti-HIV-1 agents will be used for the effective treatment of HIV/AIDS. METHOD: In continuation of our program aimed to discover anti-HIV-1 agents, twelve matrine derivatives, such as 14-formyl-15-aryloxy/methoxymatrines (3a-j) and 14-aryloxymethylidenylmatrines (3k,l), were semi-prepared from matrine, and evaluated against HIV-1 IIIB replication in acutely infected C8166 cells in vitro. RESULTS: Among them, compound 3j showed the most potent anti-HIV-1 activity with EC50 and therapeutic index (TI) values of 1.79 µg/mL, and 98.2, respectively. CONCLUSION: It has been demonstrated that the positions of methyl on the phenyl ring and 14- formylmatrine-15-oxy on the naphthyl ring were very important for the activity. It will lay the foundation for further structural modification and application of matrines as HIV-1 inhibitors.


Assuntos
Alcaloides/farmacologia , Fármacos Anti-HIV/farmacologia , Quinolizinas/farmacologia , Alcaloides/síntese química , Alcaloides/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Linhagem Celular Transformada , Descoberta de Drogas , HIV-1/efeitos dos fármacos , Humanos , Estrutura Molecular , Quinolizinas/síntese química , Quinolizinas/química , Relação Estrutura-Atividade
14.
Biochemistry ; 57(1): 136-148, 2018 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-29202246

RESUMO

Many human proteins have the potential to be developed as therapeutic agents. However, side effects caused by direct administration of natural proteins have significantly slowed expansion of protein therapeutics into the clinic. Post-translational modifications (PTMs) can improve protein properties, but because of significant knowledge gaps, we are considerably limited in our ability to apply PTMs to generate better protein therapeutics. Here, we seek to fill the gaps by studying the PTMs of a small representative chemotactic cytokine, RANTES. RANTES can inhibit HIV-1 infection by competing with it for binding to receptor CCR5 and stimulating CCR5 endocytosis. Unfortunately, RANTES can induce strong signaling, leading to severe inflammatory side effects. We apply a chemical biology approach to explore the potential of post-translationally modified RANTES as safe inhibitors of HIV-1 infection. We synthesized and systematically tested a library of RANTES isoforms for their ability to inhibit inflammatory signaling and prevent HIV-1 infection of primary human cells. Through this research, we revealed that most of the glycosylated variants have decreased inflammation-associated properties and identified one particular glyco variant, a truncated RANTES containing a Galß1-3GalNAc disaccharide α-linked to Ser4, which stands out as having the best overall properties: relatively high HIV-1 inhibition potency but also weak inflammatory properties. Moreover, our results provided a structural basis for the observed changes in the properties of RANTES. Taken together, this work highlights the potential importance of glycosylation as an alternative strategy for developing CCR5 inhibitors to treat HIV-1 infection and, more generally, for reducing or eliminating unwanted properties of therapeutic proteins.


Assuntos
Quimiocina CCL5/química , Quimiocina CCL5/farmacologia , Inibidores da Fusão de HIV/química , Inibidores da Fusão de HIV/farmacologia , HIV-1/efeitos dos fármacos , Processamento de Proteína Pós-Traducional , Acilação , Biopolímeros , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Quimiocina CCL5/efeitos adversos , Quimiocina CCL5/metabolismo , Quimiotaxia de Leucócito/efeitos dos fármacos , Glicosaminoglicanos/metabolismo , Glicosilação , Inibidores da Fusão de HIV/efeitos adversos , Inibidores da Fusão de HIV/metabolismo , Infecções por HIV/tratamento farmacológico , HIV-1/fisiologia , Humanos , Espectroscopia de Prótons por Ressonância Magnética , Receptores CCR5/metabolismo , Células THP-1
15.
Molecules ; 22(9)2017 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-28885587

RESUMO

APOBEC3G is a member of the human cytidine deaminase family that restricts Vif-deficient viruses by being packaged with progeny virions and inducing the G to A mutation during the synthesis of HIV-1 viral DNA when the progeny virus infects new cells. HIV-1 Vif protein resists the activity of A3G by mediating A3G degradation. Phorbol esters are plant-derived organic compounds belonging to the tigliane family of diterpenes and could activate the PKC pathway. In this study, we identified an inhibitor 12-O-tricosanoylphorbol-20-acetate (hop-8), a novel ester of phorbol which was isolated from Ostodes katharinae of the family Euphorbiaceae, that inhibited the replication of wild-type HIV-1 and HIV-2 strains and drug-resistant strains broadly both in C8166 cells and PBMCs with low cytotoxicity and the EC50 values ranged from 0.106 µM to 7.987 µM. One of the main mechanisms of hop-8 is to stimulate A3G expressing in HIV-1 producing cells and upregulate the A3G level in progeny virions, which results in reducing the infectivity of the progeny virus. This novel mechanism of hop-8 inhibition of HIV replication might represents a promising approach for developing new therapeutics for HIV infection.


Assuntos
Fármacos Anti-HIV/farmacologia , Euphorbiaceae/química , HIV-1/efeitos dos fármacos , Interações Hospedeiro-Patógeno , Ésteres de Forbol/farmacologia , Vírion/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Desaminase APOBEC-3G/genética , Desaminase APOBEC-3G/metabolismo , Fármacos Anti-HIV/química , Fármacos Anti-HIV/isolamento & purificação , Linhagem Celular , DNA Viral/antagonistas & inibidores , DNA Viral/biossíntese , Regulação da Expressão Gênica , HIV-1/genética , HIV-1/metabolismo , HIV-2/efeitos dos fármacos , HIV-2/genética , HIV-2/metabolismo , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/virologia , Mutação , Ésteres de Forbol/química , Ésteres de Forbol/isolamento & purificação , Extratos Vegetais/química , Cultura Primária de Células , Proteína Quinase C/genética , Proteína Quinase C/metabolismo , Transdução de Sinais , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Linfócitos T/virologia , Vírion/genética , Vírion/metabolismo , Produtos do Gene vif do Vírus da Imunodeficiência Humana/deficiência , Produtos do Gene vif do Vírus da Imunodeficiência Humana/genética
16.
J Chem Inf Model ; 57(9): 2336-2343, 2017 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-28837332

RESUMO

Protein-protein interaction between lens epithelium-derived growth factor (LEDGF/p75) and HIV-1 integrase becomes an attractive target for anti-HIV drug development. The blockade of this interaction by small molecules could potentially inhibit HIV-1 replication. These small molecules are termed as LEDGINs; and several newly identified LEDGINs have been reported to significantly reduce HIV-1 replication. Through this project, we have finished the docking screening of the Maybridge database against the p75 binding site of HIV-1 integrase using both DOCK and Autodock Vina software. Finally, we have successfully identified a novel scaffold LEDGINs inhibitor DW-D-5. Its antiviral activities and anticatalytic activity of HIV-1 integrase are similar to other LEDGINs under development. We demonstrated that the combination of DW-D-5 and FDA approved anti-HIV drugs resulted in additive inhibitory effects on HIV-1 replication, indicating that DW-D-5 could be an important component of combination pills for clinic use in HIV treatment.


Assuntos
Fármacos Anti-HIV/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Integrase de HIV/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Fármacos Anti-HIV/metabolismo , Biocatálise , Linhagem Celular , Integrase de HIV/química , HIV-1/efeitos dos fármacos , HIV-1/metabolismo , HIV-1/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/química , Simulação de Acoplamento Molecular , Ligação Proteica , Conformação Proteica , Software , Replicação Viral/efeitos dos fármacos
17.
Genome Res ; 27(9): 1608-1620, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28687705

RESUMO

Long noncoding RNAs (lncRNAs) mediate important epigenetic regulation in a wide range of biological processes and diseases. We applied comprehensive analyses of RNA-seq and CAGE-seq (cap analysis of gene expression and sequencing) to characterize the dynamic changes in lncRNA expression in rhesus macaque (Macaca mulatta) brain in four representative age groups. We identified 18 anatomically diverse lncRNA modules and 14 mRNA modules representing spatial, age, and sex specificities. Spatiotemporal- and sex-biased changes in lncRNA expression were generally higher than those observed in mRNA expression. A negative correlation between lncRNA and mRNA expression in cerebral cortex was observed and functionally validated. Our findings offer a fresh insight into spatial-, age-, and sex-biased changes in lncRNA expression in macaque brain and suggest that the changes represent a previously unappreciated regulatory system that potentially contributes to brain development and aging.


Assuntos
Epigênese Genética , Macaca mulatta/genética , Família Multigênica/genética , RNA Longo não Codificante/genética , Animais , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Feminino , Regulação da Expressão Gênica/genética , Humanos , Macaca mulatta/crescimento & desenvolvimento , Masculino , Anotação de Sequência Molecular , RNA Longo não Codificante/biossíntese , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
18.
Eur J Med Chem ; 125: 1051-1063, 2017 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-27810592

RESUMO

Currently, three HIV-1 integrase (IN) active site-directed inhibitors are in clinical use for the treatment of HIV infection. However, emergence of drug resistance mutations have limited the promise of a long-term cure. As an alternative, allosteric inhibition of IN activity has drawn great attention and several of such inhibitors are under early stage clinical development. Specifically, inhibitors of IN and the cellular cofactor LEDGF/p75 remarkably diminish proviral integration in cells and deliver a potent reduction in viral replicative capacity. Distinct from the extensively studied 2-(quinolin-3-yl) acetic acid or 1H-indol-3-yl-2-hydroxy-4-oxobut-2-enoic acid chemotypes, this study discloses a new class of selective IN-LEDGF/p75 inhibitors without the carboxylic acid functionality. More significantly, 3-hydroxypicolinamides also show low micromolar inhibition against IN dimerization, providing novel dual IN inhibitors with in vitro therapeutically selective antiviral effect for further development. Finally, our shape-based ROCS pharmacophore model of the 3-hydroxypicolinamide class of compounds provides a new insight into the binding mode of these novel IN-LEDGF/p75 inhibitors.


Assuntos
Fármacos Anti-HIV/farmacologia , Infecções por HIV/tratamento farmacológico , Integrase de HIV/metabolismo , HIV-1/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Ácidos Picolínicos/farmacologia , Mapas de Interação de Proteínas/efeitos dos fármacos , Regulação Alostérica/efeitos dos fármacos , Fármacos Anti-HIV/química , Linhagem Celular , Infecções por HIV/metabolismo , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , Humanos , Simulação de Acoplamento Molecular , Ácidos Picolínicos/química
19.
Bioorg Med Chem Lett ; 27(1): 61-65, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-27894873

RESUMO

In this study, using molecular hybridization approach, fourteen novel 2-(benzyl(4-chlorophenyl)amino)-1-(piperazin-1-yl)ethanone derivatives (7a-n) were designed as inhibitor of HIV-1 RT. The binding affinity of the designed compounds with HIV-1 RT as well as their drug-likeness behavior was predicted using in-silico studies. All the designed compounds were synthesized, characterized and in-vitro evaluated for HIV-1 RT inhibitory activity, in which tested compounds displayed significant to weak potency against the selected target. Moreover, best active compounds of the series, 7k and 7m inhibited the activity of RT with IC50 values 14.18 and 12.26µM respectively. Structure Activity Relationship (SAR) studies were also performed in order to predict the influence of substitution pattern on the RT inhibitory potency. Anti-HIV-1 and cytotoxicity studies of best five RT inhibitor (7a, 7d, 7k, 7L and 7m) revealed that, except compound 7d other compounds retained significant anti-HIV-1 potency with good safety index. Best scoring pose of compound 7m was analysed in order to predict its putative binding mode with wild HIV-1 RT.


Assuntos
Fármacos Anti-HIV/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Desenho de Fármacos , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Piperazinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Relação Dose-Resposta a Droga , Transcriptase Reversa do HIV/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade
20.
Molecules ; 21(9)2016 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-27617994

RESUMO

The search for new molecular constructs that resemble the critical two-metal binding pharmacophore and the halo-substituted phenyl functionality required for HIV-1 integrase (IN) inhibition represents a vibrant area of research within drug discovery. As reported herein, we have modified our recently disclosed 1-[2-(4-fluorophenyl)ethyl]-pyrrole-2,5-dione scaffolds to design 35 novel compounds with improved biological activities against HIV-1. These new compounds show single-digit micromolar antiviral potencies against HIV-1 and low toxicity. Among of them, compound 9g and 15i had potent anti-HIV-1 activities (EC50 < 5 µM) and excellent therapeutic index (TI, CC50/EC50 > 100). These two compounds have potential as lead compounds for further optimization into clinical anti-HIV-1 agents.


Assuntos
Fármacos Anti-HIV , Infecções por HIV/tratamento farmacológico , HIV-1/metabolismo , Pirazóis , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Infecções por HIV/metabolismo , Humanos , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacologia
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