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1.
Int J Mol Sci ; 25(11)2024 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-38891812

RESUMEN

Organophosphoate (OP) chemicals are known to inhibit the enzyme acetylcholinesterase (AChE). Studying OP poisoning is difficult because common small animal research models have serum carboxylesterase, which contributes to animals' resistance to OP poisoning. Historically, guinea pigs have been used for this research; however, a novel genetically modified mouse strain (KIKO) was developed with nonfunctional serum carboxylase (Es1 KO) and an altered acetylcholinesterase (AChE) gene, which expresses the amino acid sequence of the human form of the same protein (AChE KI). KIKO mice were injected with 1xLD50 of an OP nerve agent or vehicle control with or without atropine. After one to three minutes, animals were injected with 35 mg/kg of the currently fielded Reactivator countermeasure for OP poisoning. Postmortem brains were imaged on a Bruker RapifleX ToF/ToF instrument. Data confirmed the presence of increased acetylcholine in OP-exposed animals, regardless of treatment or atropine status. More interestingly, we detected a small amount of Reactivator within the brain of both exposed and unexposed animals; it is currently debated if reactivators can cross the blood-brain barrier. Further, we were able to simultaneously image acetylcholine, the primary affected neurotransmitter, as well as determine the location of both Reactivator and acetylcholine in the brain. This study, which utilized sensitive MALDI-MSI methods, characterized KIKO mice as a functional model for OP countermeasure development.


Asunto(s)
Acetilcolinesterasa , Modelos Animales de Enfermedad , Intoxicación por Organofosfatos , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Animales , Ratones , Humanos , Acetilcolinesterasa/metabolismo , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Atropina/farmacología , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/efectos de los fármacos , Ratones Noqueados , Inhibidores de la Colinesterasa , Acetilcolina/metabolismo
2.
Bioorg Med Chem Lett ; 73: 128891, 2022 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-35842205

RESUMEN

TYK2 is a member of the JAK family of kinases and a key mediator of IL-12, IL-23, and type I interferon signaling. These cytokines have been implicated in the pathogenesis of multiple inflammatory and autoimmune diseases such as psoriasis, rheumatoid arthritis, lupus, and inflammatory bowel diseases. Supported by compelling data from human genetic association studies, TYK2 inhibition is an attractive therapeutic strategy for these diseases. Herein, we report the discovery of a series of highly selective catalytic site TYK2 inhibitors designed using FEP+ and structurally enabled design starting from a virtual screen hit. We highlight the structure-based optimization to identify a lead candidate 30, a potent cellular TYK2 inhibitor with excellent selectivity, pharmacokinetic properties, and in vivo efficacy in a mouse psoriasis model.


Asunto(s)
Psoriasis , TYK2 Quinasa , Animales , Humanos , Quinasas Janus , Ratones , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Psoriasis/tratamiento farmacológico , Roedores
3.
Artículo en Inglés | MEDLINE | ID: mdl-38754978

RESUMEN

The addition of supplemental diets to laboratory animals, specifically rodents, is a common practice for the provision of additional nutritional support. We set out to investigate whether the use of commercially available supplemental diets during breeding affected fertility rate, litter size, pup health, and pup survival. Genetically modified female breeding mice with a C57BL/6 background were divided into 3 groups (n = 16 per group) that received standard rodent chow alone or standard rodent chow with one of 2 commercially available supplemental diets: Love Mash (Bio-Serv) extruded pellet or Nutra-Gel (Bio-Serv) diet gel. Male and female mice began receiving the supplemental diet 1 wk before being paired with a partner of the same supplemental group. The mice were allowed to breed for 1 wk before separation from the male. The dams were continued on the diet until all pups were weaned. Overall, breeding dams supplemented with the Love Mash diet experienced significantly greater reproductive success rates and pup survivability compared with the standard diet control group. Dams supplemented with either of the 2 supplemental diets supported significantly larger litters compared with the standard diet control group. Furthermore, Love Mash supplemented diet groups produced significantly larger pups compared with the Nutra-Gel supplemented groups. This study demonstrates that supplemental diets given 1 wk before breeding and continued throughout gestation, parturition, and weaning significantly improved reproductive success, increased litter sizes, and supported pup health and survival.

4.
J Med Chem ; 66(15): 10473-10496, 2023 08 10.
Artículo en Inglés | MEDLINE | ID: mdl-37427891

RESUMEN

TYK2 is a key mediator of IL12, IL23, and type I interferon signaling, and these cytokines have been implicated in the pathogenesis of multiple inflammatory and autoimmune diseases such as psoriasis, rheumatoid arthritis, lupus, and inflammatory bowel diseases. Supported by compelling data from human genome-wide association studies and clinical results, TYK2 inhibition through small molecules is an attractive therapeutic strategy to treat these diseases. Herein, we report the discovery of a series of highly selective pseudokinase (Janus homology 2, JH2) domain inhibitors of TYK2 enzymatic activity. A computationally enabled design strategy, including the use of FEP+, was instrumental in identifying a pyrazolo-pyrimidine core. We highlight the utility of computational physics-based predictions used to optimize this series of molecules to identify the development candidate 30, a potent, exquisitely selective cellular TYK2 inhibitor that is currently in Phase 2 clinical trials for the treatment of psoriasis and psoriatic arthritis.


Asunto(s)
Artritis Reumatoide , Enfermedades Autoinmunes , Psoriasis , Humanos , TYK2 Quinasa , Estudio de Asociación del Genoma Completo , Enfermedades Autoinmunes/tratamiento farmacológico , Psoriasis/tratamiento farmacológico
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