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1.
J Mater Chem B ; 11(48): 11532-11543, 2023 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-37955203

RESUMO

Circulating, soluble polymer-drug conjugates have been utilised for many years to aid the delivery of sensitive, poorly-soluble or cytotoxic drugs, prolong circulation times or minimise side effects. Long-acting therapeutics are increasing in their healthcare importance, with intramuscular and subcutaneous administration of liquid formulations being most common. Degradable implants also offer opportunities and the use of polymer-prodrug conjugates as implant materials has not been widely reported in this context. Here, the potential for polymer-prodrug conjugates of the water soluble nucleoside reverse transciption inhibitor emtricitabine (FTC) is studied. A novel diol monomer scaffold, allowing variation of prodrug substitution, has been used to form polyesters and polycarbonates by step-growth polymerisation. Materials have been screened for physical properties that enable implant formation, studied for drug release to provide mechanistic insights, and tunable prolonged release of FTC has been demonstrated over a period of at least two weeks under relevant physiological conditions.


Assuntos
Pró-Fármacos , Emtricitabina , Nucleosídeos , Polímeros , Água , RNA Polimerases Dirigidas por DNA
2.
Clin Infect Dis ; 75(Suppl 4): S510-S516, 2022 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-36410384

RESUMO

A key component of global tuberculosis (TB) control is the treatment of latent TB infection. The use of long-acting technologies to administer TB preventive treatment has the potential to significantly improve the delivery and impact of this important public health intervention. For example, an ideal long-acting treatment could consist of a single dose that could be administered in the clinic (ie, a "1-shot cure" for latent TB). Interest in long-acting formulations for TB preventive therapy has gained considerable traction in recent years. This article presents an overview of the specific considerations and current preclinical advancements relevant for the development of long-acting technologies of TB drugs for treatment of latent infection, including attributes of target product profiles, suitability of drugs for long-acting formulations, ongoing research efforts, and translation to clinical studies.


Assuntos
Tuberculose Latente , Tuberculose , Humanos , Tuberculose Latente/tratamento farmacológico , Tuberculose Latente/prevenção & controle , Tuberculose/tratamento farmacológico , Tuberculose/prevenção & controle , Antibioticoprofilaxia , Instituições de Assistência Ambulatorial , Saúde Pública
3.
Nat Commun ; 10(1): 1413, 2019 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-30926773

RESUMO

The increasing global prevalence of human immunodeficiency virus (HIV) is estimated at 36.7 million people currently infected. Lifelong antiretroviral (ARV) drug combination dosing allows management as a chronic condition by suppressing circulating viral load to allow for a near-normal life; however, the daily burden of oral administration may lead to non-adherence and drug resistance development. Long-acting (LA) depot injections of nanomilled poorly water-soluble ARVs have shown highly promising clinical results with drug exposure largely maintained over months after a single injection. ARV oral combinations rely on water-soluble backbone drugs which are not compatible with nanomilling. Here, we evaluate a unique prodrug/nanoparticle formation strategy to facilitate semi-solid prodrug nanoparticles (SSPNs) of the highly water-soluble nucleoside reverse transcriptase inhibitor (NRTI) emtricitabine (FTC), and injectable aqueous nanodispersions; in vitro to in vivo extrapolation (IVIVE) modelling predicts sustained prodrug release, with activation in relevant biological environments, representing a first step towards complete injectable LA regimens containing NRTIs.


Assuntos
Antirretrovirais/uso terapêutico , Sistemas de Liberação de Medicamentos , Infecções por HIV/tratamento farmacológico , Nanopartículas/uso terapêutico , Pró-Fármacos/uso terapêutico , Água/química , Antirretrovirais/química , Antirretrovirais/farmacocinética , Simulação por Computador , Quimioterapia Combinada , Emtricitabina/sangue , Emtricitabina/química , Emtricitabina/metabolismo , Emtricitabina/farmacocinética , Emulsões , Humanos , Pró-Fármacos/química , Solubilidade
4.
Nanoscale Adv ; 1(11): 4301-4307, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-36134394

RESUMO

The facile formation of drug nanoparticles in injectable/ingestible oils, of water-soluble antiretroviral tenofovir disoproxil fumarate, using a novel nanoprecipitation is presented with studies showing drug release into relevant aqueous media.

5.
Clin Pharmacokinet ; 57(2): 255-266, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28540638

RESUMO

BACKGROUND AND OBJECTIVES: Long-acting injectable antiretrovirals represent a pharmacological alternative to oral formulations and an innovative clinical option to address adherence and reduce drug costs. Clinical studies in children and adolescents are characterised by ethical and logistic barriers complicating the identification of dose optimisation. Physiologically-based pharmacokinetic modelling represents a valuable tool to inform dose finding prior to clinical trials. The objective of this study was to simulate potential dosing strategies for existing long-acting injectable depot formulations of cabotegravir and rilpivirine in children and adolescents (aged 3-18 years) using physiologically-based pharmacokinetic modelling. METHODS: Whole-body physiologically-based pharmacokinetic models were developed to represent the anatomical, physiological and molecular processes and age-related changes in children and adolescents through allometric equations. Models were validated for long-acting injectable intramuscular cabotegravir and rilpivirine in adults. Subsequently, the anatomy and physiology of children and adolescents were validated against available literature. The optimal doses of monthly administration of cabotegravir and rilpivirine were identified in children and adolescents, to achieve trough concentrations over the target concentrations derived in a recent efficacy trial of the same formulations. RESULTS: Pharmacokinetic data generated through the physiologically-based pharmacokinetic simulations were similar to observed clinical data in adults. Optimal doses of long-acting injectable antiretrovirals cabotegravir and rilpivirine were predicted using the release rate observed for existing clinical formulations, for different weight groups of children and adolescents. The intramuscular loading dose and maintenance dose of cabotegravir ranged from 200 to 600 mg and from 100 to 250 mg, respectively, and for rilpivirine it ranged from 250 to 550 mg and from 150 to 500 mg, respectively, across various weight groups of children ranging from 15 to 70 kg. CONCLUSIONS: The reported findings represent a rational platform for the identification of suitable dosing strategies and can inform prospective clinical investigation of long-acting injectable formulations in children and adolescents.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Simulação por Computador , Piridonas/administração & dosagem , Rilpivirina/administração & dosagem , Adolescente , Fatores Etários , Fármacos Anti-HIV/farmacocinética , Peso Corporal , Criança , Pré-Escolar , Preparações de Ação Retardada , Relação Dose-Resposta a Droga , Liberação Controlada de Fármacos , Humanos , Modelos Biológicos , Piridonas/farmacocinética , Rilpivirina/farmacocinética
6.
Biochemistry ; 55(7): 1135-48, 2016 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-26813608

RESUMO

Bacimethrin (4-amino-5-hydroxymethyl-2-methoxypyrimidine), a natural product isolated from some bacteria, has been implicated as an inhibitor of bacterial and yeast growth, as well as in inhibition of thiamin biosynthesis. Given that thiamin biosynthetic enzymes could convert bacimethrin to 2'-methoxythiamin diphosphate (MeOThDP), it is important to evaluate the effect of this coenzyme analogue on thiamin diphosphate (ThDP)-dependent enzymes. The potential functions of MeOThDP were explored on five ThDP-dependent enzymes: the human and Escherichia coli pyruvate dehydrogenase complexes (PDHc-h and PDHc-ec, respectively), the E. coli 1-deoxy-D-xylulose 5-phosphate synthase (DXPS), and the human and E. coli 2-oxoglutarate dehydrogenase complexes (OGDHc-h and OGDHc-ec, respectively). Using several mechanistic tools (fluorescence, circular dichroism, kinetics, and mass spectrometry), it was demonstrated that MeOThDP binds in the active centers of ThDP-dependent enzymes, however, with a binding mode different from that of ThDP. While modest activities resulted from addition of MeOThDP to E. coli PDHc (6-11%) and DXPS (9-14%), suggesting that MeOThDP-derived covalent intermediates are converted to the corresponding products (albeit with rates slower than that with ThDP), remarkably strong activity (up to 75%) resulted upon addition of the coenzyme analogue to PDHc-h. With PDHc-ec and PDHc-h, the coenzyme analogue could support all reactions, including communication between components in the complex. No functional substitution of MeOThDP for ThDP was in evidence with either OGDH-h or OGDH-ec, shown to be due to tight binding of ThDP.


Assuntos
Proteínas de Escherichia coli/metabolismo , Modelos Moleculares , Complexo Piruvato Desidrogenase/metabolismo , Tiamina Pirofosfato/análogos & derivados , Tiamina Pirofosfato/metabolismo , Transferases/metabolismo , Substituição de Aminoácidos , Apoenzimas/química , Apoenzimas/genética , Apoenzimas/metabolismo , Ligação Competitiva , Biocatálise , Domínio Catalítico , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/genética , Humanos , Complexo Cetoglutarato Desidrogenase/química , Complexo Cetoglutarato Desidrogenase/genética , Complexo Cetoglutarato Desidrogenase/metabolismo , Mutação , Subunidades Proteicas/química , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Pirimidinas/química , Complexo Piruvato Desidrogenase/química , Complexo Piruvato Desidrogenase/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Especificidade por Substrato , Transferases/química
7.
J Med Chem ; 57(11): 4521-31, 2014 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-24786226

RESUMO

Atg8 is a ubiquitin-like autophagy protein in eukaryotes that is covalently attached (lipidated) to the elongating autophagosomal membrane. Autophagy is increasingly appreciated as a target in diverse diseases from cancer to eukaryotic parasitic infections. Some of the autophagy machinery is conserved in the malaria parasite, Plasmodium. Although Atg8's function in the parasite is not well understood, it is essential for Plasmodium growth and survival and partially localizes to the apicoplast, an indispensable organelle in apicomplexans. Here, we describe the identification of inhibitors from the Malaria Medicine Venture Malaria Box against the interaction of PfAtg8 with its E2-conjugating enzyme, PfAtg3, by surface plasmon resonance. Inhibition of this protein-protein interaction prevents PfAtg8 lipidation with phosphatidylethanolamine. These small molecule inhibitors share a common scaffold and have activity against both blood and liver stages of infection by Plasmodium falciparum. We have derivatized this scaffold into a functional platform for further optimization.


Assuntos
Antimaláricos/química , Bases de Dados de Compostos Químicos , Plasmodium falciparum/efeitos dos fármacos , Proteínas de Protozoários/antagonistas & inibidores , Antimaláricos/farmacologia , Sítios de Ligação , Sangue , Estágios do Ciclo de Vida , Fígado/parasitologia , Plasmodium falciparum/fisiologia , Proteínas de Protozoários/química , Proteínas de Protozoários/metabolismo , Piridinas/química , Piridinas/farmacologia , Tiazóis/química , Tiazóis/farmacologia
8.
Medchemcomm ; 4(1): 130-134, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23509611

RESUMO

Stable IspF substrate analogs were synthesized. In the presence of substrate analogs, the E. coli IspF-MEP complex shows activities distinct from IspF, and bisphosphonates (BP) behave differently than their diphosphate (DP) counterparts. Bisphosphonate analogs activate and/or stabilize IspF, and only the closest structural substrate analog weakly inhibits the IspF-MEP complex.

9.
ACS Chem Biol ; 7(10): 1702-10, 2012 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-22839733

RESUMO

There is significant progress toward understanding catalysis throughout the essential MEP pathway to isoprenoids in human pathogens; however, little is known about pathway regulation. The present study begins by testing the hypothesis that isoprenoid biosynthesis is regulated via feedback inhibition of the fifth enzyme cyclodiphosphate synthase IspF by downstream isoprenoid diphosphates. Here, we demonstrate recombinant E. coli IspF is not inhibited by downstream metabolites isopentenyl diphosphate (IDP), dimethylallyl diphosphate (DMADP), geranyl diphosphate (GDP), and farnesyl diphosphate (FDP) under standard assay conditions. However, 2C-methyl-d-erythritol 4-phosphate (MEP), the product of reductoisomerase IspC and first committed MEP pathway intermediate, activates and sustains this enhanced IspF activity, and the IspF-MEP complex is inhibited by FDP. We further show that the methylerythritol scaffold itself, which is unique to this pathway, drives the activation and stabilization of active IspF. Our results suggest a novel feed-forward regulatory mechanism for 2C-methyl-d-erythritol 2,4-cyclodiphosphate (MEcDP) production and support an isoprenoid biosynthesis regulatory mechanism via feedback inhibition of the IspF-MEP complex by FDP. The results have important implications for development of inhibitors against the IspF-MEP complex, which may be the physiologically relevant form of the enzyme.


Assuntos
Eritritol/análogos & derivados , Proteínas de Escherichia coli/metabolismo , Fósforo-Oxigênio Liases/metabolismo , Fosfatos Açúcares/farmacologia , Catálise , Inibidores Enzimáticos/farmacologia , Eritritol/farmacologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/enzimologia , Proteínas de Escherichia coli/antagonistas & inibidores , Guanosina Difosfato/farmacologia , Cinética , Fósforo-Oxigênio Liases/antagonistas & inibidores , Fosfatos de Poli-Isoprenil/farmacologia , Sesquiterpenos/farmacologia , Terpenos/metabolismo
10.
Medchemcomm ; 3: 65-67, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23326631

RESUMO

DXP synthase catalyzes the formation of 1-deoxy-D-xylulose 5-phosphate, an essential precursor in pathogen isoprenoid biosynthesis. The selective inhibition of this ThDP-dependent transformation is a challenging goal in the development of isoprenoid biosynthesis inhibitors. Potent, selective inhibitors could lead to new anti-infective agents. Here, we demonstrate selective inhibition of E. coli DXP synthase by butylacetylphosphonate.

11.
J Biol Chem ; 286(42): 36522-31, 2011 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-21878632

RESUMO

Emerging resistance of human pathogens to anti-infective agents make it necessary to develop new agents to treat infection. The methylerythritol phosphate pathway has been identified as an anti-infective target, as this essential isoprenoid biosynthetic pathway is widespread in human pathogens but absent in humans. The first enzyme of the pathway, 1-deoxy-D-xylulose 5-phosphate (DXP) synthase, catalyzes the formation of DXP via condensation of D-glyceraldehyde 3-phosphate (D-GAP) and pyruvate in a thiamine diphosphate-dependent manner. Structural analysis has revealed a unique domain arrangement suggesting opportunities for the selective targeting of DXP synthase; however, reports on the kinetic mechanism are conflicting. Here, we present the results of tryptophan fluorescence binding and kinetic analyses of DXP synthase and propose a new model for substrate binding and mechanism. Our results are consistent with a random sequential kinetic mechanism, which is unprecedented in this enzyme class.


Assuntos
Aldose-Cetose Isomerases/química , Proteínas de Escherichia coli/química , Escherichia coli/enzimologia , Modelos Químicos , Complexos Multienzimáticos/química , Oxirredutases/química , Aldose-Cetose Isomerases/genética , Aldose-Cetose Isomerases/metabolismo , Catálise , Farmacorresistência Bacteriana/fisiologia , Escherichia coli/genética , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Humanos , Cinética , Complexos Multienzimáticos/genética , Complexos Multienzimáticos/metabolismo , Oxirredutases/genética , Oxirredutases/metabolismo , Estrutura Terciária de Proteína
12.
Org Lett ; 11(20): 4748-51, 2009 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-19778006

RESUMO

A study of DXP synthase has revealed flexibility in the acceptor substrate binding pocket for nonpolar substrates and has uncovered new details of the catalytic mechanism to show that pyruvate can act as both donor and acceptor substrate.


Assuntos
Transferases/metabolismo , Aldeídos/metabolismo , Biocatálise , Cromatografia Líquida de Alta Pressão , Escherichia coli/enzimologia , Piruvatos/metabolismo , Especificidade por Substrato
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