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1.
Nat Commun ; 12(1): 3061, 2021 05 24.
Artículo en Inglés | MEDLINE | ID: mdl-34031399

RESUMEN

The SARS-CoV-2 pandemic has triggered global efforts to develop therapeutics. The main protease of SARS-CoV-2 (Mpro), critical for viral replication, is a key target for therapeutic development. An organoselenium drug called ebselen has been demonstrated to have potent Mpro inhibition and antiviral activity. We have examined the binding modes of ebselen and its derivative in Mpro via high resolution co-crystallography and investigated their chemical reactivity via mass spectrometry. Stronger Mpro inhibition than ebselen and potent ability to rescue infected cells were observed for a number of derivatives. A free selenium atom bound with cysteine of catalytic dyad has been revealed in crystallographic structures of Mpro with ebselen and MR6-31-2 suggesting hydrolysis of the enzyme bound organoselenium covalent adduct and formation of a phenolic by-product, confirmed by mass spectrometry. The target engagement with selenation mechanism of inhibition suggests wider therapeutic applications of these compounds against SARS-CoV-2 and other zoonotic beta-corona viruses.


Asunto(s)
Azoles/farmacología , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Compuestos de Organoselenio/farmacología , SARS-CoV-2/enzimología , Antivirales/farmacología , Azoles/química , Dominio Catalítico , Proteasas 3C de Coronavirus/metabolismo , Cristalografía por Rayos X , Cisteína/química , Hidrólisis , Isoindoles , Modelos Moleculares , Compuestos de Organoselenio/química , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Estándares de Referencia , SARS-CoV-2/efectos de los fármacos , Salicilanilidas/química , Salicilanilidas/farmacología , Selenio/metabolismo
2.
Commun Biol ; 3(1): 97, 2020 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-32139772

RESUMEN

Mutations to the gene encoding superoxide dismutase-1 (SOD1) were the first genetic elements discovered that cause motor neuron disease (MND). These mutations result in compromised SOD1 dimer stability, with one of the severest and most common mutations Ala4Val (A4V) displaying a propensity to monomerise and aggregate leading to neuronal death. We show that the clinically used ebselen and related analogues promote thermal stability of A4V SOD1 when binding to Cys111 only. We have developed a A4V SOD1 differential scanning fluorescence-based assay on a C6S mutation background that is effective in assessing suitability of compounds. Crystallographic data show that the selenium atom of these compounds binds covalently to A4V SOD1 at Cys111 at the dimer interface, resulting in stabilisation. This together with chemical amenability for hit expansion of ebselen and its on-target SOD1 pharmacological chaperone activity holds remarkable promise for structure-based therapeutics for MND using ebselen as a template.


Asunto(s)
Azoles/química , Azoles/farmacología , Diseño de Fármacos , Enfermedad de la Neurona Motora/tratamiento farmacológico , Compuestos de Organoselenio/química , Compuestos de Organoselenio/farmacología , Superóxido Dismutasa-1 , Sustitución de Aminoácidos/genética , Azoles/síntesis química , Azoles/uso terapéutico , Cristalografía por Rayos X , Descubrimiento de Drogas/métodos , Evaluación Preclínica de Medicamentos/métodos , Humanos , Isoindoles , Modelos Moleculares , Chaperonas Moleculares/síntesis química , Chaperonas Moleculares/química , Chaperonas Moleculares/uso terapéutico , Simulación del Acoplamiento Molecular , Enfermedad de la Neurona Motora/genética , Enfermedad de la Neurona Motora/metabolismo , Enfermedad de la Neurona Motora/patología , Proteínas Mutantes/química , Proteínas Mutantes/efectos de los fármacos , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutación Missense , Compuestos de Organoselenio/síntesis química , Compuestos de Organoselenio/aislamiento & purificación , Compuestos de Organoselenio/uso terapéutico , Pliegue de Proteína/efectos de los fármacos , Multimerización de Proteína/efectos de los fármacos , Estabilidad Proteica/efectos de los fármacos , Estructura Terciaria de Proteína , Compuestos de Azufre/síntesis química , Compuestos de Azufre/química , Superóxido Dismutasa-1/química , Superóxido Dismutasa-1/efectos de los fármacos , Superóxido Dismutasa-1/genética , Superóxido Dismutasa-1/metabolismo , Termodinámica
3.
Sci Adv ; 3(9): eaao1551, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28959730

RESUMEN

Lymphatic filariasis and onchocerciasis are two important neglected tropical diseases (NTDs) that cause severe disability. Control efforts are hindered by the lack of a safe macrofilaricidal drug. Targeting the Wolbachia bacterial endosymbionts in these parasites with doxycycline leads to a macrofilaricidal outcome, but protracted treatment regimens and contraindications restrict its widespread implementation. The Anti-Wolbachia consortium aims to develop improved anti-Wolbachia drugs to overcome these barriers. We describe the first screening of a large, diverse compound library against Wolbachia. This whole-organism screen, streamlined to reduce bottlenecks, produced a hit rate of 0.5%. Chemoinformatic analysis of the top 50 hits led to the identification of six structurally diverse chemotypes, the disclosure of which could offer interesting avenues of investigation to other researchers active in this field. An example of hit-to-lead optimization is described to further demonstrate the potential of developing these high-quality hit series as safe, efficacious, and selective anti-Wolbachia macrofilaricides.


Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Evaluación Preclínica de Medicamentos/métodos , Bibliotecas de Moléculas Pequeñas , Wolbachia/efectos de los fármacos , Análisis por Conglomerados , Biología Computacional/métodos , Descubrimiento de Drogas/métodos , Humanos , Reproducibilidad de los Resultados , Flujo de Trabajo
4.
AIDS ; 29(18): 2385-95, 2015 Nov 28.
Artículo en Inglés | MEDLINE | ID: mdl-26372480

RESUMEN

OBJECTIVE: Exposure to abacavir is associated with T-cell-mediated hypersensitivity reactions in individuals carrying human leukocyte antigen (HLA)-B57 : 01. To activate T cells, abacavir interacts directly with endogenous HLA-B57 : 01 and HLA-B57 : 01 expressed on the surface of antigen presenting cells. We have investigated whether chemical modification of abacavir can produce a molecule with antiviral activity that does not bind to HLA-B57 : 01 and activate T cells. DESIGN: An interdisciplinary laboratory study using samples from human donors expressing HLA-B57 : 01. Researchers were blinded to the analogue structures and modelling data. METHODS: Sixteen 6-amino substituted abacavir analogues were synthesized. Computational docking studies were completed to predict capacity for analogue binding within HLA-B57 : 01. Abacavir-responsive CD8 clones were generated to study the association between HLA-B57 : 01 analogue binding and T-cell activation. Antiviral activity and the direct inhibitory effect of analogues on proliferation were assessed. RESULTS: Major histocompatibility complex class I-restricted CD8 clones proliferated and secreted IFNγ following abacavir binding to surface and endogenous HLA-B57 : 01. Several analogues retained antiviral activity and showed no overt inhibitory effect on proliferation, but displayed highly divergent antigen-driven T-cell responses. For example, abacavir and N-propyl abacavir were equally potent at activating clones, whereas the closely related analogues N-isopropyl and N-methyl isopropyl abacavir were devoid of T-cell activity. Docking abacavir analogues to HLA-B57 : 01 revealed a quantitative relationship between drug-protein binding and the T-cell response. CONCLUSION: These studies demonstrate that the unwanted T-cell activity of abacavir can be eliminated whilst maintaining the favourable antiviral profile. The in-silico model provides a tool to aid the design of safer antiviral agents that may not require a personalized medicines approach to therapy.


Asunto(s)
Fármacos Anti-VIH/efectos adversos , Linfocitos T CD8-positivos/inmunología , Didesoxinucleósidos/efectos adversos , Hipersensibilidad a las Drogas/prevención & control , Infecciones por VIH/tratamiento farmacológico , Antígenos HLA-B/metabolismo , Fármacos Anti-VIH/química , Fármacos Anti-VIH/metabolismo , Fármacos Anti-VIH/farmacología , Didesoxinucleósidos/química , Didesoxinucleósidos/metabolismo , Didesoxinucleósidos/farmacología , Humanos , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Unión Proteica
5.
Proc Natl Acad Sci U S A ; 112(3): 755-60, 2015 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-25564664

RESUMEN

Cytochrome bc1 is a proven drug target in the prevention and treatment of malaria. The rise in drug-resistant strains of Plasmodium falciparum, the organism responsible for malaria, has generated a global effort in designing new classes of drugs. Much of the design/redesign work on overcoming this resistance has been focused on compounds that are presumed to bind the Q(o) site (one of two potential binding sites within cytochrome bc1 using the known crystal structure of this large membrane-bound macromolecular complex via in silico modeling. Cocrystallization of the cytochrome bc1 complex with the 4(1H)-pyridone class of inhibitors, GSK932121 and GW844520, that have been shown to be potent antimalarial agents in vivo, revealed that these inhibitors do not bind at the Q(o) site but bind at the Q(i )site. The discovery that these compounds bind at the Q(i) site may provide a molecular explanation for the cardiotoxicity and eventual failure of GSK932121 in phase-1 clinical trial and highlight the need for direct experimental observation of a compound bound to a target site before chemical optimization and development for clinical trials. The binding of the 4(1H)-pyridone class of inhibitors to Q(i) also explains the ability of this class to overcome parasite Q(o)-based atovaquone resistance and provides critical structural information for future design of new selective compounds with improved safety profiles.


Asunto(s)
Antimaláricos/metabolismo , Complejo III de Transporte de Electrones/metabolismo , Piridonas/metabolismo , Sitios de Unión , Complejo III de Transporte de Electrones/química , Simulación del Acoplamiento Molecular
6.
ChemMedChem ; 6(11): 2094-108, 2011 Nov 04.
Artículo en Inglés | MEDLINE | ID: mdl-21905228

RESUMEN

Four different series of triazole diamidines have been prepared by the Pinner method from the corresponding triazole dinitriles. Copper-catalyzed "click chemistry" was used for the synthesis of 1,4- and 4,5-substituted triazoles, aryl magnesium acetylide reagents for the 1,5-substituted triazoles, with a thermal dipolar addition reaction employed for the 2,4-substituted triazoles. In vitro antimalarial activity against two different PfCRT-modified parasite lines (Science 2002, 298, 210-213) of Plasmodium falciparum and inhibition of hemozoin formation were determined for each compound. Several diamidines with potent nanomolar antimalarial activities were identified, and selected molecules were resynthesized as their diamidoxime triazole prodrugs. One of these prodrugs, OB216, proved to be highly potent in vivo with an ED50 value of 5 mg kg(-1) (po) and an observed 100 % cure rate (CD100) of just 10 mg kg(-1) by oral (po) administration in mice infected with P. vinckei.


Asunto(s)
Antimaláricos/química , Antimaláricos/farmacología , Benzamidinas/química , Triazoles/química , Animales , Química Clic , Evaluación Preclínica de Medicamentos , Femenino , Hemoproteínas/metabolismo , Malaria/tratamiento farmacológico , Ratones , Plasmodium falciparum/efectos de los fármacos , Triazoles/farmacología
7.
J Med Chem ; 52(5): 1408-15, 2009 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-19222165

RESUMEN

N-tert-Butyl isoquine (4) (GSK369796) is a 4-aminoquinoline drug candidate selected and developed as part of a public-private partnership between academics at Liverpool, MMV, and GSK pharmaceuticals. This molecule was rationally designed based on chemical, toxicological, pharmacokinetic, and pharmacodynamic considerations and was selected based on excellent activity against Plasmodium falciparum in vitro and rodent malaria parasites in vivo. The optimized chemistry delivered this novel synthetic quinoline in a two-step procedure from cheap and readily available starting materials. The molecule has a full industry standard preclinical development program allowing first into humans to proceed. Employing chloroquine (1) and amodiaquine (2) as comparator molecules in the preclinical plan, the first preclinical dossier of pharmacokinetic, toxicity, and safety pharmacology has also been established for the 4-aminoquinoline antimalarial class. These studies have revealed preclinical liabilities that have never translated into the human experience. This has resulted in the availability of critical information to other drug development teams interested in developing antimalarials within this class.


Asunto(s)
Aminoquinolinas/farmacología , Antimaláricos/farmacología , Bencilaminas/farmacología , Aminoquinolinas/síntesis química , Aminoquinolinas/química , Aminoquinolinas/farmacocinética , Aminoquinolinas/toxicidad , Amodiaquina/análogos & derivados , Animales , Antimaláricos/síntesis química , Antimaláricos/farmacocinética , Antimaláricos/toxicidad , Bencilaminas/síntesis química , Bencilaminas/química , Bencilaminas/toxicidad , Inhibidores Enzimáticos del Citocromo P-450 , Perros , Evaluación Preclínica de Medicamentos , Resistencia a Medicamentos , Femenino , Haplorrinos , Hemo/química , Humanos , Malaria/tratamiento farmacológico , Ratones , Modelos Moleculares , Plasmodium berghei/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Plasmodium yoelii , Ratas , Relación Estructura-Actividad
8.
J Pharm Sci ; 98(1): 362-77, 2009 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18563832

RESUMEN

The disposition of three 4-aminoquinoline leads, namely isoquine (ISO), des-ethyl isoquine (DEI) and N-tert-butyl isoquine (NTBI), were studied in a range of in vivo and in vitro assays to assist in selecting an appropriate candidate for further development. Analogous to amodiaquine (ADQ), ISO undergoes oxidative N-dealkylation to form DEI in vivo. Blood clearance of DEI was as much as 10-fold lower than that of ISO in animals and after oral administration, metabolite exposure exceeded that of parent by as much as 14-fold. Replacement of the N-ethyl with an N-tert-butyl substituent substantially reduced N-dealkylation as blood clearance of NTBI was approximately 2 to 3-fold lower than DEI in mouse, rat, dog and monkey. Mean NTBI oral bioavailability was generally higher than the other leads (>/=68%). Blood cell association was substantial for NTBI, particularly in dog and monkey, where blood to plasma concentration ratios >4 were observed. Human plasma protein binding was similar for NTBI, DEI, and des-ethyl amodiaquine (DEA). Allometric scaling predicted human blood clearance (CL) for NTBI to be low ( approximately 12% liver blood flow). All the 4-aminoquinolines inhibited recombinant human cytochrome P450 2D6 with similar potency; DEI also inhibited 1A2. On balance, NTBI appeared the most promising lead to progress towards full development.


Asunto(s)
Aminoquinolinas/farmacocinética , Antimaláricos/farmacocinética , Aminoquinolinas/sangre , Aminoquinolinas/metabolismo , Animales , Antimaláricos/sangre , Antimaláricos/metabolismo , Disponibilidad Biológica , Perros , Evaluación Preclínica de Medicamentos/métodos , Femenino , Humanos , Macaca fascicularis , Masculino , Ratones , Ratas , Ratas Sprague-Dawley , Especificidad de la Especie
9.
J Biol Chem ; 282(13): 9372-9382, 2007 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-17227762

RESUMEN

Artemisinin and its derivatives are currently recommended as first-line antimalarials in regions where Plasmodium falciparum is resistant to traditional drugs. The cytotoxic activity of these endoperoxides toward rapidly dividing human carcinoma cells and cell lines has been reported, and it is hypothesized that activation of the endoperoxide bridge by an iron(II) species, to form C-centered radicals, is essential for cytotoxicity. The studies described here have utilized artemisinin derivatives, dihydroartemisinin, 10beta-(p-bromophenoxy)dihydroartemisinin, and 10beta-(p-fluorophenoxy)dihydroartemisinin, to determine the chemistry of endoperoxide bridge activation to reactive intermediates responsible for initiating cell death and to elucidate the molecular mechanism of cell death. These studies have demonstrated the selective cytotoxic activity of the endoperoxides toward leukemia cell lines (HL-60 and Jurkat) over quiescent peripheral blood mononuclear cells. Deoxy-10beta-(p-fluorophenoxy)dihydroartemisinin, which lacks the endoperoxide bridge, was 50- and 130-fold less active in HL-60 and Jurkat cells, respectively, confirming the importance of this functional group for cytotoxicity. We have shown that chemical activation is responsible for cytotoxicity by using liquid chromatography-mass spectrometry analysis to monitor endoperoxide activation by measurement of a stable rearrangement product of endoperoxide-derived radicals, which was formed in sensitive HL-60 cells but not in insensitive peripheral blood mononuclear cells. In HL-60 cells the endoperoxides induce caspase-dependent apoptotic cell death characterized by concentration- and time-dependent mitochondrial membrane depolarization, activation of caspases-3 and -7, sub-G(0)/G(1) DNA formation, and attenuation by benzyloxycarbonyl-VAD-fluoromethyl ketone, a caspase inhibitor. Overall, these results indicate that endoperoxide-induced cell death is a consequence of activation of the endoperoxide bridge to radical species, which triggers caspase-dependent apoptosis.


Asunto(s)
Apoptosis/efectos de los fármacos , Artemisia , Artemisininas/toxicidad , Sesquiterpenos/toxicidad , Antimaláricos/toxicidad , Artemisia/química , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/metabolismo , Radicales Libres/metabolismo , Radicales Libres/toxicidad , Células HL-60 , Humanos , Células Jurkat , L-Lactato Deshidrogenasa/metabolismo , Sales de Tetrazolio/química , Sales de Tetrazolio/metabolismo , Tiazoles/química , Tiazoles/metabolismo
10.
Expert Opin Investig Drugs ; 14(9): 1117-28, 2005 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16144496

RESUMEN

Artemisinin derivatives such as artesunate, dihydroartemisinin and artemether are playing an increasing role in the treatment of drug-resistant malaria. They are the most potent antimalarials available, rapidly killing all asexual stages of the parasite Plasmodium falciparum. This review highlights the recent developments in the area of improved second-generation semi-synthetic artemisinin derivatives and fully synthetic antimalarial endoperoxide drugs. In pursuit of synthetic analogues of the artemisinins, one of the major challenges for chemists in this area has been the non-trivial development of techniques for the introduction of the peroxide bridge into candidate drugs. Although chemical research has enabled chemists to incorporate the endoperoxide 'warhead' into synthetic analogues of artemisinin, significant drawbacks with many candidates have included comparatively poor antimalarial activity, non-stereoselective syntheses and chemical approaches that are not readily amenable to scale up. However, very recent progress with synthetic 1,2,4-trioxolanes provides a new benchmark for future medicinal chemistry efforts in this area.


Asunto(s)
Antimaláricos/síntesis química , Antimaláricos/uso terapéutico , Artemisininas/síntesis química , Artemisininas/uso terapéutico , Malaria/tratamiento farmacológico , Sesquiterpenos/síntesis química , Sesquiterpenos/uso terapéutico , Animales , Antimaláricos/farmacología , Artemisininas/farmacología , Humanos , Malaria/parasitología , Peróxidos/síntesis química , Peróxidos/uso terapéutico , Sesquiterpenos/farmacología
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