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1.
Eur J Med Chem ; 242: 114693, 2022 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-36049274

RESUMEN

Mutations in the Leucine Rich Repeat Protein Kinase 2 gene (LRRK2) are genetic predispositions for Parkinson's Disease, of which the G2019S (GS) missense mutation is the most common. GS-LRRK2 has a hyperactive kinase, and although numerous drug discovery programs have targeted the LRRK2 kinase, few have reached clinical trials. We recently reported on the discovery of a novel LRRK2 kinase inhibitor chemotype, 1H-pyrazole biaryl sulfonamides. Although both potent and selective GS-LRRK2 inhibitors, 1H-pyrazole biaryl sulfonamides are incapable of crossing the blood-brain barrier. Retaining the core 1H-pyrazole and focusing our efforts on a phenylsulfonamide bioisosteric replacement, we report the discovery and preliminary development of azaspirocyclic 1H-3,4,5-trisubstituted pyrazoles as potent and selective (>2000-fold) GS-LRRK2 kinase inhibitors capable of entering rodent brain. The compounds disclosed here present an excellent starting point for the development of more brain penetrant compounds.


Asunto(s)
Enfermedad de Parkinson , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/metabolismo , Mutación , Enfermedad de Parkinson/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/metabolismo , Pirazoles/farmacología , Pirazoles/uso terapéutico , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico
2.
ACS Med Chem Lett ; 13(6): 981-988, 2022 Jun 09.
Artículo en Inglés | MEDLINE | ID: mdl-35707141

RESUMEN

G2019S (GS) is the most prevalent mutation in the leucine rich repeat protein kinase 2 gene (LRRK2), a genetic predisposition that is common for Parkinson's disease, as well as for some forms of cancer, and is a shared risk allele for Crohn's disease. GS-LRRK2 has a hyperactive kinase, and although numerous drug discovery programs have targeted LRRK2 kinase, few have reached clinical development. We report the discovery and preliminary development of an entirely novel structural class of potent and selective GS-LRRK2 kinase inhibitors: biaryl-1H-pyrazoles.

3.
Eur J Med Chem ; 229: 114080, 2022 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-34992038

RESUMEN

Mutations in the Leucine Rich Repeat Protein Kinase 2 gene (LRRK2) are the most common genetic causes of Parkinson's Disease (PD). The G2019S mutation is the most common inherited LRRK2 mutation, occurs in the kinase domain, and results in increased kinase activity. We report the discovery and development of compound 38, an indazole-based, G2019S-selective (>2000-fold vs. WT) LRRK2 inhibitor capable of entering rodent brain (Kp = 0.5) and selectively inhibiting G2019S-LRRK2. The compounds disclosed herein present a starting point for further development of brain penetrant G2019S selective inhibitors that hopefully reduce lung phenotype side-effects and pave the way to providing a precision medicine for people with PD who carry the G2019S mutation.


Asunto(s)
Indazoles/síntesis química , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/antagonistas & inhibidores , Fármacos Neuroprotectores/síntesis química , Enfermedad de Parkinson/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/síntesis química , Animales , Encéfalo , Modelos Animales de Enfermedad , Descubrimiento de Drogas , Humanos , Indazoles/farmacocinética , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Pulmón , Masculino , Ratones , Simulación del Acoplamiento Molecular , Mutación , Fármacos Neuroprotectores/farmacocinética , Fenotipo , Unión Proteica , Conformación Proteica , Inhibidores de Proteínas Quinasas/farmacocinética , Roedores , Relación Estructura-Actividad
4.
PLoS One ; 15(5): e0233117, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32396550

RESUMEN

Severe acute respiratory illness (SARI) is a major cause of death and morbidity in low- and middle-income countries, however, the etiologic agents are often undetermined due to the lack of molecular diagnostics in hospitals and clinics. To examine evidence for select viral infections among patients with SARI in northern Vietnam, we studied 348 nasopharyngeal samples from military and civilian patients admitted to 4 hospitals in the greater Hanoi area from 2017-2019. Initial screening for human respiratory viral pathogens was performed in Hanoi, Vietnam at the National Institute of Hygiene and Epidemiology (NIHE) or the Military Institute of Preventative Medicine (MIPM), and an aliquot was shipped to Duke-NUS Medical School in Singapore for validation. Patient demographics were recorded and used to epidemiologically describe the infections. Among military and civilian cases of SARI, 184 (52.9%) tested positive for one or more respiratory viruses. Influenza A virus was the most prevalent virus detected (64.7%), followed by influenza B virus (29.3%), enterovirus (3.8%), adenovirus (1.1%), and coronavirus (1.1%). Risk factor analyses demonstrated an increased risk of influenza A virus detection among military hospital patients (adjusted OR, 2.0; 95% CI, 1.2-3.2), and an increased risk of influenza B virus detection among patients enrolled in year 2017 (adjusted OR, 7.9; 95% CI, 2.7-22.9). As influenza A and B viruses were commonly associated with SARI and are treatable, SARI patients entering these hospitals would benefit if the hospitals were able to adapt onsite molecular diagnostics.


Asunto(s)
Neumonía/epidemiología , Síndrome Respiratorio Agudo Grave/epidemiología , Síndrome Respiratorio Agudo Grave/virología , Adolescente , Adulto , Coronavirus/aislamiento & purificación , Enterovirus/aislamiento & purificación , Femenino , Humanos , Virus de la Influenza A/aislamiento & purificación , Virus de la Influenza B/aislamiento & purificación , Gripe Humana/epidemiología , Gripe Humana/virología , Masculino , Persona de Mediana Edad , Instalaciones Militares/estadística & datos numéricos , Neumonía/virología , Vietnam/epidemiología , Adulto Joven
5.
Nature ; 579(7798): 303-308, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31945771

RESUMEN

Arrestin proteins bind to active, phosphorylated G-protein-coupled receptors (GPCRs), thereby preventing G-protein coupling, triggering receptor internalization and affecting various downstream signalling pathways1,2. Although there is a wealth of structural information detailing the interactions between GPCRs and G proteins, less is known about how arrestins engage GPCRs. Here we report a cryo-electron microscopy structure of full-length human neurotensin receptor 1 (NTSR1) in complex with truncated human ß-arrestin 1 (ßarr1(ΔCT)). We find that phosphorylation of NTSR1 is critical for the formation of a stable complex with ßarr1(ΔCT), and identify phosphorylated sites in both the third intracellular loop and the C terminus that may promote this interaction. In addition, we observe a phosphatidylinositol-4,5-bisphosphate molecule forming a bridge between the membrane side of NTSR1 transmembrane segments 1 and 4 and the C-lobe of arrestin. Compared with a structure of a rhodopsin-arrestin-1 complex, in our structure arrestin is rotated by approximately 85° relative to the receptor. These findings highlight both conserved aspects and plasticity among arrestin-receptor interactions.


Asunto(s)
Modelos Moleculares , Receptores de Neurotensina/química , beta-Arrestina 1/química , Microscopía por Crioelectrón , Humanos , Fosforilación , Estabilidad Proteica , Estructura Cuaternaria de Proteína , Receptores de Neurotensina/metabolismo , beta-Arrestina 1/metabolismo
6.
Nat Cancer ; 1(2): 184-196, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-33768207

RESUMEN

2'3'-cyclic GMP-AMP (cGAMP) is an intracellular second messenger that is synthesized in response to cytosolic double-stranded DNA and activates the innate immune STING pathway. Our previous discovery of its extracellular hydrolase ENPP1 hinted at the existence of extracellular cGAMP. Here, we detected that cGAMP is continuously exported but then efficiently cleared by ENPP1, explaining why it has previously escaped detection. By developing potent, specific, and cell impermeable ENPP1 inhibitors, we found that cancer cells continuously export cGAMP in culture at steady state and at higher levels when treated with ionizing radiation (IR). In mouse tumors, depletion of extracellular cGAMP decreased tumor-associated immune cell infiltration and abolished the curative effect of IR. Boosting extracellular cGAMP with ENPP1 inhibitors synergized with IR to delay tumor growth. In conclusion, extracellular cGAMP is an anti-cancer immunotransmitter that could be harnessed to treat cancers with low immunogenicity.


Asunto(s)
Neoplasias , Nucleótidos Cíclicos , Animales , Ratones , Neoplasias/radioterapia , Nucleótidos Cíclicos/genética , Sistemas de Mensajero Secundario
7.
Telemed J E Health ; 20(5): 493-5, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24611518

RESUMEN

Medical surveillance data from all government health clinics in Vietnam are currently collected through a slow, paper-driven process. Short message service (SMS) technology delivered through mobile phones offers a simple solution to improving the speed through which disease surveillance information can be collected. Identifying health concerns earlier with this mobile-based disease surveillance system has the potential to improve the care for patients seen at community health clinics as well as predict more quickly that a medical emergency, such as a pandemic, will occur. Thus, we piloted the feasibility of an SMS-based disease surveillance system designed for healthcare workers in Vietnam to directly report disease information on diarrhea and influenza-like illness to a central data repository using their mobile phones and an intuitive, user-friendly platform. This article reports data from 1,579 patient data entries in 20 Vietnamese health clinics during a 6-month period.


Asunto(s)
Teléfono Celular/estadística & datos numéricos , Encuestas Epidemiológicas/métodos , Registros Médicos/estadística & datos numéricos , Telecomunicaciones/organización & administración , Telemedicina/estadística & datos numéricos , Instituciones de Atención Ambulatoria/estadística & datos numéricos , Servicios de Salud Comunitaria/organización & administración , Países en Desarrollo , Diarrea/diagnóstico , Diarrea/epidemiología , Estudios de Factibilidad , Femenino , Humanos , Gripe Humana/diagnóstico , Gripe Humana/epidemiología , Masculino , Evaluación de Necesidades , Proyectos Piloto , Estadística como Asunto , Vietnam
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