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1.
Viruses ; 12(8)2020 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-32722574

RESUMO

COVID-19 is a pandemic health emergency faced by the entire world. The clinical treatment of the severe acute respiratory syndrome (SARS) CoV-2 is currently based on the experimental administration of HIV antiviral drugs, such as lopinavir, ritonavir, and remdesivir (a nucleotide analogue used for Ebola infection). This work proposes a repurposing process using a database containing approximately 8000 known drugs in synergy structure- and ligand-based studies by means of the molecular docking and descriptor-based protocol. The proposed in silico findings identified new potential SARS CoV-2 main protease (MPRO) inhibitors that fit in the catalytic binding site of SARS CoV-2 MPRO. Several selected structures are NAD-like derivatives, suggesting a relevant role of these molecules in the modulation of SARS CoV-2 infection in conditions of cell chronic oxidative stress. Increased catabolism of NAD(H) during protein ribosylation in the DNA damage repair process may explain the greater susceptibility of the elderly population to the acute respiratory symptoms of COVID-19. The molecular modelling studies proposed herein agree with this hypothesis.


Assuntos
Antivirais/química , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/enzimologia , Infecções por Coronavirus/tratamento farmacológico , Cisteína Endopeptidases/química , NAD/metabolismo , Pandemias , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química , Envelhecimento/metabolismo , Sítios de Ligação , Simulação por Computador , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Dano ao DNA , Reposicionamento de Medicamentos , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacologia , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Oxirredução , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Inibidores de Proteases/química
2.
PLoS One ; 15(7): e0235483, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32697773

RESUMO

A series of potent HIV-1 protease inhibitors, containing diverse piperidine analogues as the P2-ligands, 4-substituted phenylsulfonamides as the P2'-ligands and a hydrophobic cyclopropyl group as the P1'-ligand, were designed, synthesized and evaluated in this work. Among these twenty-four target compounds, many of them exhibited excellent activity against HIV-1 protease with half maximal inhibitory concentration (IC50) values below 20 nM. Particularly, compound 22a containing a (R)-piperidine-3-carboxamide as the P2-ligand and a 4-methoxylphenylsulfonamide as the P2'-ligand exhibited the most effective inhibitory activity with an IC50 value of 3.61 nM. More importantly, 22a exhibited activity with inhibition of 42% and 26% against wild-type and Darunavir (DRV)-resistant HIV-1 variants, respectively. Additionally, the molecular docking of 22a with HIV-1 protease provided insight into the ligand-binding properties, which was of great value for further study.


Assuntos
Inibidores Enzimáticos/química , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/química , HIV-1/efeitos dos fármacos , Piperidinas/farmacologia , Cristalografia por Raios X , Darunavir/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Infecções por HIV/virologia , Protease de HIV/química , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/farmacologia , HIV-1/química , HIV-1/patogenicidade , Humanos , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacologia
3.
Artigo em Inglês | MEDLINE | ID: mdl-32371328

RESUMO

INTRODUCTION: Ultrafiltration (UF) is used to separate unbound drugs; however, non-specific binding (NSB) may be a limiting factor of this technique. Pretreatment of UF devices has been suggested to reduce NSB. Therefore, the pretreatment methodologies for UF devices were evaluated in order to test their effectiveness in reducing NSB of protease inhibitors (PIs). METHODOLOGY: Two PIs (lopinavir-LPV and ritonavir-RTV) were tested. UF devices were pretreated with ultrapure water, Tween-20 or Tween-80. To evaluate the NSB, after UF devices being pretreated, ultrafiltrate solutions containing the analytes at two concentrations (low and high) were used. Samples were quantified by LC-MS/MS. RESULTS: UF devices pretreated with Tween-5% had the lowest NSB for both analytes. NSB values varied between 7 and 11% at low concentration 16-34% at high LPV concentration, respectively. For RTV, NSB was approximately 6% for low concentration and 18% for high concentration. Failure to completely remove Tween in UF devices could results in an overestimation of NSB. CONCLUSION: Pretreatment of UF device with Tween and subsequent removal proved to be effective in reducing NSB of PI.


Assuntos
Inibidores da Protease de HIV/química , Lopinavir/química , Ritonavir/química , Ultrafiltração/métodos , Ligação Competitiva , Cromatografia Líquida de Alta Pressão , Humanos , Plasma/química , Ligação Proteica , Padrões de Referência , Espectrometria de Massas em Tandem
4.
Travel Med Infect Dis ; 35: 101646, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32294562

RESUMO

BACKGROUND: The COVID-19 has now been declared a global pandemic by the World Health Organization. There is an emergent need to search for possible medications. METHOD: Utilization of the available sequence information, homology modeling, and in slico docking a number of available medications might prove to be effective in inhibiting the SARS-CoV-2 two main drug targets, the spike glycoprotein, and the 3CL protease. RESULTS: Several compounds were determined from the in silico docking models that might prove to be effective inhibitors for SARS-CoV-2. Several antiviral medications: Zanamivir, Indinavir, Saquinavir, and Remdesivir show potential as and 3CLPRO main proteinase inhibitors and as a treatment for COVID-19. CONCLUSION: Zanamivir, Indinavir, Saquinavir, and Remdesivir are among the exciting hits on the 3CLPRO main proteinase. It is also exciting to uncover that Flavin Adenine Dinucleotide (FAD) Adeflavin, B2 deficiency medicine, and Coenzyme A, a coenzyme, may also be potentially used for the treatment of SARS-CoV-2 infections. The use of these off-label medications may be beneficial in the treatment of the COVID-19.


Assuntos
Betacoronavirus/química , Infecções por Coronavirus/virologia , Cisteína Endopeptidases/química , Descoberta de Drogas/métodos , Pneumonia Viral/virologia , Glicoproteína da Espícula de Coronavírus/química , Proteínas não Estruturais Virais/química , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/química , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/química , Alanina/uso terapêutico , Sítios de Ligação , Infecções por Coronavirus/tratamento farmacológico , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/uso terapêutico , Humanos , Indinavir/química , Indinavir/uso terapêutico , Simulação de Acoplamento Molecular , Uso Off-Label , Pandemias , Pneumonia Viral/tratamento farmacológico , Saquinavir/química , Saquinavir/uso terapêutico , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Homologia Estrutural de Proteína , Proteínas não Estruturais Virais/antagonistas & inibidores , Zanamivir/química , Zanamivir/uso terapêutico
5.
Acta Crystallogr D Struct Biol ; 76(Pt 3): 302-310, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32133994

RESUMO

Twinning is a crystal-growth anomaly in which protein monomers exist in different orientations but are related in a specific way, causing diffraction reflections to overlap. Twinning imposes additional symmetry on the data, often leading to the assignment of a higher symmetry space group. Specifically, in merohedral twinning, reflections from each monomer overlap and require a twin law to model unique structural data from overlapping reflections. Neglecting twinning in the crystallographic analysis of quasi-rotationally symmetric homo-oligomeric protein structures can mask the degree of structural non-identity between monomers. In particular, any deviations from perfect symmetry will be lost if higher than appropriate symmetry is applied during crystallographic analysis. Such cases warrant choosing between the highest symmetry space group possible or determining whether the monomers have distinguishable structural asymmetries and thus require a lower symmetry space group and a twin law. Using hexagonal cocrystals of HIV-1 protease, a C2-symmetric homodimer whose symmetry is broken by bound ligand, it is shown that both assigning a lower symmetry space group and applying a twin law during refinement are critical to achieving a structural model that more accurately fits the electron density. By re-analyzing three recently published HIV-1 protease structures, improvements in nearly every crystallographic metric are demonstrated. Most importantly, a procedure is demonstrated where the inhibitor can be reliably modeled in a single orientation. This protocol may be applicable to many other homo-oligomers in the PDB.


Assuntos
HIV-1/enzimologia , Produtos do Gene gag do Vírus da Imunodeficiência Humana/química , Cristalografia por Raios X , Inibidores da Protease de HIV/química , Modelos Moleculares
6.
J Enzyme Inhib Med Chem ; 35(1): 629-638, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32037904

RESUMO

Phialophora verrucosa causes several fungal human diseases, mainly chromoblastomycosis, which is extremely difficult to treat. Several studies have shown that human immunodeficiency virus peptidase inhibitors (HIV-PIs) are attractive candidates for antifungal therapies. This work focused on studying the action of HIV-PIs on peptidase activity secreted by P. verrucosa and their effects on fungal proliferation and macrophage interaction. We detected a peptidase activity from P. verrucosa able to cleave albumin, sensitive to pepstatin A and HIV-PIs, especially lopinavir, ritonavir and amprenavir, showing for the first time that this fungus secretes aspartic-type peptidase. Furthermore, lopinavir, ritonavir and nelfinavir reduced the fungal growth, causing remarkable ultrastructural alterations. Lopinavir and ritonavir also affected the conidia-macrophage adhesion and macrophage killing. Interestingly, P. verrucosa had its growth inhibited by ritonavir combined with either itraconazole or ketoconazole. Collectively, our results support the antifungal action of HIV-PIs and their relevance as a possible alternative therapy for fungal infections.


Assuntos
Antifúngicos/farmacologia , Ácido Aspártico Proteases/antagonistas & inibidores , Inibidores da Protease de HIV/farmacologia , Macrófagos/efeitos dos fármacos , Phialophora/efeitos dos fármacos , Antifúngicos/síntese química , Antifúngicos/química , Ácido Aspártico Proteases/metabolismo , Carbamatos/síntese química , Carbamatos/química , Carbamatos/farmacologia , Relação Dose-Resposta a Droga , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/química , Humanos , Lopinavir/síntese química , Lopinavir/química , Lopinavir/farmacologia , Macrófagos/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Phialophora/enzimologia , Phialophora/crescimento & desenvolvimento , Ritonavir/síntese química , Ritonavir/química , Ritonavir/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacologia
7.
Eur J Med Chem ; 186: 111900, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31771827

RESUMO

Since dual inhibitors may yield lower toxicity and reduce the likelihood of drug resistance, as well as inhibitors of HIV-1 PR and RT constitute the core of chemotherapy for AIDS treatment, we herein designed and synthesized new coumarin derivatives characterized by various linkers that exhibited excellent potency against PR and a weak inhibition of RT. Among which, compounds 6f and 7c inhibited PR with IC50 values of 15.5 and 62.1 nM, respectively, and weakly affected also RT with IC50 values of 241.8 and 188.7 µM, respectively, showing the possibility in the future of developing dual HIV-1 PR/RT inhibitors. Creative stimulation for further research of more potent dual HIV-1 inhibitors was got according to the molecular docking studies.


Assuntos
Fármacos Anti-HIV/farmacologia , Cumarínicos/farmacologia , Inibidores da Protease de HIV/farmacologia , Protease de HIV/metabolismo , Transcriptase Reversa do HIV/antagonistas & inibidores , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Linhagem Celular , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/química , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade
8.
J Chem Theory Comput ; 16(2): 1284-1299, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-31877249

RESUMO

Over the past several decades, atomistic simulations of biomolecules, whether carried out using molecular dynamics or Monte Carlo techniques, have provided detailed insights into their function. Comparing the results of such simulations for a few closely related systems has guided our understanding of the mechanisms by which changes such as ligand binding or mutation can alter the function. The general problem of detecting and interpreting such mechanisms from simulations of many related systems, however, remains a challenge. This problem is addressed here by applying supervised and unsupervised machine learning techniques to a variety of thermodynamic observables extracted from molecular dynamics simulations of different systems. As an important test case, these methods are applied to understand the evasion by human immunodeficiency virus type-1 (HIV-1) protease of darunavir, a potent inhibitor to which resistance can develop via the simultaneous mutation of multiple amino acids. Complex mutational patterns have been observed among resistant strains, presenting a challenge to developing a mechanistic picture of resistance in the protease. In order to dissect these patterns and gain mechanistic insight into the role of specific mutations, molecular dynamics simulations were carried out on a collection of HIV-1 protease variants, chosen to include highly resistant strains and susceptible controls, in complex with darunavir. Using a machine learning approach that takes advantage of the hierarchical nature in the relationships among the sequence, structure, and function, an integrative analysis of these trajectories reveals key details of the resistance mechanism, including changes in the protein structure, hydrogen bonding, and protein-ligand contacts.


Assuntos
Farmacorresistência Viral , Protease de HIV/metabolismo , HIV-1/enzimologia , Ligantes , Aprendizado de Máquina , Protease de HIV/química , Protease de HIV/genética , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/metabolismo , Humanos , Ligação de Hidrogênio , Simulação de Dinâmica Molecular , Método de Monte Carlo , Mutação , Ligação Proteica , Eletricidade Estática
9.
BMC Complement Altern Med ; 19(1): 351, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31805905

RESUMO

BACKGROUND: Acquired immunodeficiency syndrome (AIDS) is caused by the Human immunodeficiency virus type-1 (HIV-1). HIV-1 protease (HIV-1 PR) is an essential enzyme for the HIV replication, and therefore, it is an important target for antiretroviral drugs development, particularly from natural products. Auricularia polytricha (AP) is an edible mushroom with several important therapeutic properties. These properties will be investigated as HIV-1 PR inhibitors. METHODS: The sequential hexane (APH), ethanol (APE) and water (APW) extracts from AP were screened for inhibitory activity against HIV-1 PR. The extract that consistently showed the strong HIV-1 PR inhibition was further investigated for its phytochemical constituents. The compounds were purified by column chromatography. The isolated compounds were structurally elucidated using 1D and 2D NMR, HRMS, FTIR, and GC/MS techniques. Each compound was screened against HIV-1 PR to determine its inhibitory activity and to provide an explanation for the activity found in the extract. RESULTS: Hexane crude extract of AP (APH) exhibited significant inhibition on HIV-1 PR activity. Four major compounds isolated from APH fraction were identified to be two triacylglycerols, linoleic acid and ergosterol. Moreover, all four compounds showed significant inhibition of HIV-1 PR activity. CONCLUSION: The findings from this study suggest that AP is a good source of fatty esters, fatty acids and ergosterol. These natural products exhibit anti-HIV-1 properties by blocking HIV-1 PR. These important biological results warrant further development of AP as an alternative antiretroviral drug.


Assuntos
Agaricales/química , Produtos Biológicos/farmacologia , Inibidores da Protease de HIV/farmacologia , Protease de HIV/efeitos dos fármacos , Células 3T3-L1 , Animais , Produtos Biológicos/química , Produtos Biológicos/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Ergosterol , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/toxicidade , HIV-1/efeitos dos fármacos , Ácido Linoleico , Camundongos , Triglicerídeos
10.
Molecules ; 24(24)2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31835661

RESUMO

In this study, we isolated nine compounds from the acid hydrolysate of the flower buds of Lonicera fulvotomentosa Hsu et S. C. Cheng and characterized their chemical structures using 1H-NMR, 13C-NMR, and electron ionization mass spectroscopy (EI-MS). These compounds were identified as ß-sitosterol (1), 5,5'-dibutoxy-2,2'-bifuran (2), nonacosane-10-ol (3), ethyl (3ß)-3,23-dihydroxyolean-12-en-28-oate (4), oleanolic acid (5), ethyl caffeate (6), caffeic acid (7), isovanillin (8), and hederagenin (9), with 4 as a new triterpene compound. Inhibitory activity against human immunodeficiency virus (HIV) protease was also evaluated for the compounds, and only ethyl caffeate, caffeic acid, and isovanillin (6, 7, and 8) exhibited inhibitory effects, with IC50 values of 1.0 µM, 1.5 µM, and 3.5 µM, respectively. Molecular docking with energy minimization and subsequent molecular dynamic (MD) simulation showed that ethyl caffeate and caffeic acid bound to the active site of HIV protease, while isovanillin drifted out from the active site and dissociated into bulk water during MD simulations, and most of the binding residues of HIV protease have been previously identified for HIV protease inhibitors. These results suggest that caffeic acid derivatives may possess inhibitory activities towards HIV protease other than previously reported inhibitory activities against HIV integrase, and thus ethyl caffeate and caffeic acid could be used as lead compounds in developing potential HIV protease inhibitors, and possibly even dual-function inhibitors against HIV.


Assuntos
Inibidores da Protease de HIV/farmacologia , Protease de HIV/metabolismo , HIV-1/enzimologia , Lonicera/química , Compostos Fitoquímicos/farmacologia , Domínio Catalítico , Protease de HIV/química , Inibidores da Protease de HIV/química , Espectrometria de Massas , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Compostos Fitoquímicos/química , Extratos Vegetais/análise
11.
J Enzyme Inhib Med Chem ; 34(1): 1451-1456, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31409143

RESUMO

Herein, we report the effect of nine FDA approved protease inhibitor drugs against a new HIV-1 subtype C mutant protease, E35D↑G↑S. The mutant has five mutations, E35D, two insertions, position 36 (G and S), and D60E. Kinetics, inhibition constants, vitality, Gibbs free binding energies are reported. The variant showed a decreased affinity for substrate and low catalytic efficiency compared to the wild type. There was a significant decrease in the binding of seven FDA approved protease inhibitors against the mutant (p < .0001). Amprenavir and ritonavir showed the least decrease, but still significant reduced activity in comparison to the wildtype (4 and 5 folds, respectively, p = .0021 and .003, respectively). Nelfinavir and atazanavir were the worst inhibitors against the variant as seen from the IC50, with values of 1401 ± 3.0 and 685 ± 3.0 nM, respectively. Thermodynamics data showed less favourable Gibbs free binding energies for the protease inhibitors to the mutant.


Assuntos
Inibidores da Protease de HIV/farmacologia , Protease de HIV/efeitos dos fármacos , HIV-1/enzimologia , Termodinâmica , Protease de HIV/genética , Protease de HIV/metabolismo , Inibidores da Protease de HIV/química , Concentração Inibidora 50 , Cinética , Simulação de Acoplamento Molecular , Mutação
12.
Curr Top Med Chem ; 19(18): 1571-1598, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31237209

RESUMO

Acquired Immunodeficiency Syndrome (AIDS) is a chronic disease characterized by multiple life-threatening illnesses caused by a retro-virus, Human Immunodeficiency Virus (HIV). HIV infection slowly destroys the immune system and increases the risk of various other infections and diseases. Although, there is no immediate cure for HIV infection/AIDS, several drugs targeting various cruxes of HIV infection are used to slow down the progress of the disease and to boost the immune system. One of the key therapeutic strategies is Highly Active Antiretroviral Therapy (HAART) or ' AIDS cocktail' in a general sense, which is a customized combination of anti-retroviral drugs designed to combat the HIV infection. Since HAART's inception in 1995, this treatment was found to be effective in improving the life expectancy of HIV patients over two decades. Among various classes of HAART treatment regimen, Protease Inhibitors (PIs) are known to be widely used as a major component and found to be effective in treating HIV infection/AIDS. For the past several years, a variety of protease inhibitors have been reported. This review outlines the drug design strategies of PIs, chemical and pharmacological characteristics of some mechanism-based inhibitors, summarizes the recent developments in small molecule based drug discovery with HIV protease as a drug target. Further discussed are the pharmacology, PI drug resistance on HIV PR, adverse effects of HIV PIs and challenges/impediments in the successful application of HIV PIs as an important class of drugs in HAART regimen for the effective treatment of AIDS.


Assuntos
Síndrome de Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/farmacologia , Inibidores da Protease de HIV/farmacologia , Protease de HIV/metabolismo , HIV/efeitos dos fármacos , Fármacos Anti-HIV/química , Inibidores da Protease de HIV/química , Humanos
13.
J Biomol NMR ; 73(6-7): 365-374, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31243634

RESUMO

Over the last two decades, both the sensitivity of NMR and the time scale of molecular dynamics (MD) simulation have increased tremendously and have advanced the field of protein dynamics. HIV-1 protease has been extensively studied using these two methods, and has presented a framework for cross-evaluation of structural ensembles and internal dynamics by integrating the two methods. Here, we review studies from our laboratories over the last several years, to understand the mechanistic basis of protease drug-resistance mutations and inhibitor responses, using NMR and crystal structure-based parallel MD simulations. Our studies demonstrate that NMR relaxation experiments, together with crystal structures and MD simulations, significantly contributed to the current understanding of structural/dynamic changes due to HIV-1 protease drug resistance mutations.


Assuntos
Inibidores da Protease de HIV/química , Protease de HIV/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ressonância Magnética Nuclear Biomolecular , Sítios de Ligação , Farmacorresistência Viral , Protease de HIV/genética , Protease de HIV/metabolismo , Inibidores da Protease de HIV/farmacologia , Humanos , Mutação , Ligação Proteica , Relação Estrutura-Atividade , Água/química
14.
Artigo em Inglês | MEDLINE | ID: mdl-31061155

RESUMO

There is currently no specific therapeutics for the HIV-1-related central nervous system (CNS) complications. Here we report that three newly designed CNS-targeting HIV-1 protease inhibitors (PIs), GRL-083-13, GRL-084-13, and GRL-087-13, which contain a P1-3,5-bis-fluorophenyl or P1-para-monofluorophenyl ring, and P2-bis-tetrahydrofuran (bis-THF) or P2-tetrahydropyrano-tetrahydrofuran (Tp-THF), with a sulfonamide isostere, are highly active against wild-type HIV-1 strains and primary clinical isolates (50% effective concentration [EC50], 0.0002 to ∼0.003 µM), with minimal cytotoxicity. These CNS-targeting PIs efficiently suppressed the replication of HIV-1 variants (EC50, 0.002 to ∼0.047 µM) that had been selected to propagate at high concentrations of conventional HIV-1 PIs. Such CNS-targeting PIs maintained their antiviral activity against HIV-2ROD as well as multidrug-resistant clinical HIV-1 variants isolated from AIDS patients who no longer responded to existing antiviral regimens after long-term therapy. Long-term drug selection experiments revealed that the emergence of resistant-HIV-1 against these CNS-targeting PIs was substantially delayed. In addition, the CNS-targeting PIs showed the most favorable CNS penetration properties among the tested compounds, including various FDA-approved anti-HIV-1 drugs, as assessed with the in vitro blood-brain barrier reconstruction system. Crystallographic analysis demonstrated that the bicyclic rings at the P2 moiety of the CNS-targeting PIs form strong hydrogen-bond interactions with HIV-1 protease (PR) active site. Moreover, both the P1-3,5-bis-fluorophenyl and P1-para-monofluorophenyl rings sustain greater van der Waals contacts with PR than in the case of darunavir (DRV). The data suggest that the present CNS-targeting PIs have desirable features for treating patients infected with wild-type and/or multidrug-resistant HIV-1 strains and might serve as promising preventive and/or therapeutic candidates for HIV-1-associated neurocognitive disorders (HAND) and other CNS complications.


Assuntos
Viroses do Sistema Nervoso Central/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/virologia , Barreira Hematoencefálica/efeitos dos fármacos , Domínio Catalítico , Viroses do Sistema Nervoso Central/virologia , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos/métodos , Farmacorresistência Viral/efeitos dos fármacos , Infecções por HIV/complicações , Infecções por HIV/virologia , Protease de HIV/química , Protease de HIV/metabolismo , HIV-1/isolamento & purificação , HIV-1/fisiologia , HIV-2/efeitos dos fármacos , Humanos , Ratos , Sulfonamidas/química , Replicação Viral/efeitos dos fármacos
15.
Biol Pharm Bull ; 42(2): 261-267, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30713256

RESUMO

A series of tetraethyl 2,4,8,10-tetramethyl-6,12-diaryl-3,9-dioxahexacyclo[6.4.0.02,7.04,11.05,10]dodecane-1,5,7,11-tetracarboxylates (simplified as 3,9-dioxatetraasteranes) with C2-symmetric structural characteristics were synthesized through the [2 + 2] photocycloaddition of the diethyl 2,6-dimethyl-4-aryl-4H-pyran-3,5-dicarboxylates. Besides, their anti-human immunodeficiency virus (HIV)-1 activities were evaluated by enzyme-linked immunosorbent assay (ELISA) assay against HIV-1 (IIIB) replication in MT-4 cell culture. The result showed that the tested compounds exhibited potential activates with IC50 values less than 110 nM. Furthermore, docking study was carried out to study the binding mode of these compounds. The results indicated that the overall orientation of the inhibitors in the active site were similar to that of the cyclic urea AHA001 and a hydrogen bond with the protein residues might play a crucial role in their anti-HIV-1 activities. Such results will provide a theoretical foundation for further investigations on the biological activity of 3,9-dioxatetraasteranes.


Assuntos
Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacologia , Urease/química , Urease/farmacologia , Azepinas/química , Azepinas/farmacologia , Protease de HIV/metabolismo , Inibidores da Protease de HIV/síntese química , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/química , Ureia/farmacologia , Urease/síntese química
16.
Eur J Pharm Sci ; 131: 153-158, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30790704

RESUMO

The main objective of this study was to evaluate the pharmacokinetics of ritonavir (RTV) nanosuspension in rats in both fed and fasted state in comparison with coarse powder, physical mixture and commercial product (Norvir®). The point to point relation model was generated between the results of in vitro dissolution and in vivo pharmacokinetic studies. The oral RTV nanosuspension was prepared with microfluidization method. Nanosuspension was obtained with 540-550 nm of particle size, 0.1-0.4 of particle size distribution and about -20 mV of zeta potential values. According to in vivo pharmacokinetic studies in rats, Cmax and AUC0-t values in nanosuspension displayed an 8.9- and 12.5-fold increase compared to the coarse powder, and a 1.9- and 2.1-fold increase compared to the commercial product, respectively in the fed group. The point to point relation model showed that the correlation model was significant. It is concluded that nanosuspension is a promising drug delivery system to enhance oral bioavailability of ritonavir.


Assuntos
Inibidores da Protease de HIV/farmacocinética , Nanopartículas/administração & dosagem , Ritonavir/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Liberação Controlada de Fármacos , Jejum/metabolismo , Inibidores da Protease de HIV/sangue , Inibidores da Protease de HIV/química , Derivados da Hipromelose/química , Masculino , Nanopartículas/química , Ratos Wistar , Ritonavir/sangue , Ritonavir/química , Dodecilsulfato de Sódio/química , Suspensões
17.
Arch Virol ; 164(4): 949-960, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30680529

RESUMO

HIV is one of the most lethal viral diseases in the human population. Patients often suffer from drug resistance, which hampers HIV therapy. Eleven different structural analogues of saquinavir (SQV), designed using ChemSketch™ and named S1 through S11, were compared with SQV with respect to their pharmacodynamic and pharmacokinetic properties. Pharmacokinetic predictions were carried out using AutoDock, and molecular docking between macromolecule HIV protease (PDB ID: 3IXO) and analogues S1 - S11 as ligands was performed. Analogues S1, S3, S4, S9 and S11 had lower binding scores when compared with saquinavir, whereas that of analogue S5 was similar. Pharmacokinetic predictions made using ACDilab2, including the Lipinski profile, general physical features, absorption, distribution, metabolism and excretion parameters, and toxicity values, for the eleven analogues and SQV suggested that S1 and S5 are pharmacodynamically and pharmacokinetically robust molecules that could be developed and established as lead molecules after in vitro and in vivo studies.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacocinética , HIV-1/enzimologia , Saquinavir/análogos & derivados , Saquinavir/farmacocinética , Animais , Infecções por HIV/virologia , Protease de HIV/química , Protease de HIV/genética , Protease de HIV/metabolismo , Inibidores da Protease de HIV/administração & dosagem , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Humanos , Camundongos , Simulação de Acoplamento Molecular , Saquinavir/administração & dosagem
18.
J Comput Aided Mol Des ; 33(2): 287-294, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30564994

RESUMO

The COMBINE method was designed to study congeneric series of compounds including structural information of ligand-protein complexes. Although very successful, the method has not received the same level of attention than other alternatives to study Quantitative Structure Active Relationships (QSAR) mainly because lack of ways to measure the uncertainty of the predictions and the need for large datasets. Active learning, a semi-supervised learning approach that makes use of uncertainty to enhance models' performance while reducing the size of the training sets, has been used in this work to address both problems. We propose two estimators of uncertainty: the pool of regressors and the distance to the training set. The performance of the methods has been evaluated by testing the resulting active learning workflows in 3 diverse datasets: HIV-1 protease inhibitors, Taxol-derivatives and BRD4 inhibitors. The proposed strategies were successful in 80% of the cases for the taxol-derivatives and BRD4 inhibitors, while outperformed random selection in the case of the HIV-1 protease inhibitors time-split. Our results suggest that AL-COMBINE might be an effective way of producing consistently superior QSAR models with a limited number of samples.


Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Inibidores da Protease de HIV/química , Paclitaxel/análogos & derivados , Paclitaxel/química , Relação Quantitativa Estrutura-Atividade , Fatores de Transcrição/antagonistas & inibidores , Proteínas de Ciclo Celular/química , Bases de Dados de Compostos Químicos , Bases de Dados de Proteínas , Protease de HIV/química , Ligantes , Estrutura Molecular , Aprendizagem Baseada em Problemas , Termodinâmica , Fatores de Transcrição/química , Incerteza
19.
Bioorg Med Chem Lett ; 29(3): 357-361, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30580917

RESUMO

The design, synthesis and SAR study of a new series of HIV-1 protease inhibitors with pentacyclic triterpenoids as P2 ligands and phenylsulfonamide as P2' ligands were discussed. These compounds exhibited micromolar inhibitory potency, among which compound T1c displayed HIV-1 protease inhibition with IC50 values of 0.12 µM, which was 67 times the inhibitory activity of its raw material Ursolic acid (8.0 µM).


Assuntos
Fármacos Anti-HIV/farmacologia , Desenho de Fármacos , Inibidores da Protease de HIV/farmacologia , Protease de HIV/metabolismo , Triterpenos Pentacíclicos/farmacologia , Sulfonamidas/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Relação Dose-Resposta a Droga , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/química , HIV-1/efeitos dos fármacos , Humanos , Ligantes , Testes de Sensibilidade Microbiana , Estrutura Molecular , Triterpenos Pentacíclicos/síntese química , Triterpenos Pentacíclicos/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
20.
Biochem J ; 476(2): 375-384, 2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30573649

RESUMO

HIV protease is essential for processing the Gag polyprotein to produce infectious virions and is a major target in antiretroviral therapy. We have identified an unusual HIV-1 subtype C variant that contains insertions of leucine and asparagine (L38↑N↑L) in the hinge region of protease at position 38. This was isolated from a protease inhibitor naïve infant. Isothermal titration calorimetry showed that 10% less of L38↑N↑L protease was in the active conformation as compared with a reference strain. L38↑N↑L protease displayed a ±50% reduction in K M and k cat The catalytic efficiency (k cat/K M) of L38↑N↑L protease was not significantly different from that of wild type although there was a 42% reduction in specific activity for the variant. An in vitro phenotypic assay showed the L38↑N↑L protease to be susceptible to lopinavir (LPV), atazanavir (ATV) and darunavir in the context of an unrelated Gag. However, in the presence of the related Gag, L38↑N↑L showed reduced susceptibility to darunavir while remaining susceptible to LPV and ATV. Furthermore, a reduction in viral replication capacity (RC) was observed in combination with the related Gag. The reduced susceptibility to darunavir and decrease in RC may be due to PTAPP duplication in the related Gag. The present study shows the importance of considering the Gag region when looking at drug susceptibility of HIV-1 protease variants.


Assuntos
Darunavir/química , Inibidores da Protease de HIV/química , Protease de HIV/química , Protease de HIV/genética , HIV-1 , Lopinavir/química , Mutagênese Insercional , Produtos do Gene gag do Vírus da Imunodeficiência Humana/química , Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética , Darunavir/farmacologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/enzimologia , Infecções por HIV/genética , Protease de HIV/metabolismo , HIV-1/enzimologia , HIV-1/genética , Humanos , Lopinavir/farmacologia , Produtos do Gene gag do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Produtos do Gene gag do Vírus da Imunodeficiência Humana/metabolismo
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