The protein Keap1 is central to the regulation of the Nrf2-mediated cytoprotective response, and is increasingly recognized as an important target for therapeutic intervention in a range of diseases ...involving excessive oxidative stress and inflammation. The BTB domain of Keap1 plays key roles in sensing environmental electrophiles and in mediating interactions with the Cul3/Rbx1 E3 ubiquitin ligase system, and is believed to be the target for several small molecule covalent activators of the Nrf2 pathway. However, despite structural information being available for several BTB domains from related proteins, there have been no reported crystal structures of Keap1 BTB, and this has precluded a detailed understanding of its mechanism of action and interaction with antagonists. We report here the first structure of the BTB domain of Keap1, which is thought to contain the key cysteine residue responsible for interaction with electrophiles, as well as structures of the covalent complex with the antagonist CDDO/bardoxolone, and of the constitutively inactive C151W BTB mutant. In addition to providing the first structural confirmation of antagonist binding to Keap1 BTB, we also present biochemical evidence that adduction of Cys 151 by CDDO is capable of inhibiting the binding of Cul3 to Keap1, and discuss how this class of compound might exert Nrf2 activation through disruption of the BTB-Cul3 interface.
DNA-encoded chemical library technology was developed with the vision of its becoming a transformational platform for drug discovery. The hope was that a new paradigm for the discovery of ...low-molecular-weight drugs would be enabled by combining the vast molecular diversity achievable with combinatorial chemistry, the information-encoding attributes of DNA, the power of molecular biology, and a streamlined selection-based discovery process. Here, we describe the discovery and early clinical development of GSK2256294, an inhibitor of soluble epoxide hydrolase (sEH, EPHX2), by using encoded-library technology (ELT). GSK2256294 is an orally bioavailable, potent and selective inhibitor of sEH that has a long half life and produced no serious adverse events in a first-time-in-human clinical study. To our knowledge, GSK2256294 is the first molecule discovered from this technology to enter human clinical testing and represents a realization of the vision that DNA-encoded chemical library technology can efficiently yield molecules with favorable properties that can be readily progressed into high-quality drugs.
Keap Calm, and Carry on Covalently Wilson, Anthony J; Kerns, Jeffrey K; Callahan, James F ...
Journal of medicinal chemistry,
10/2013, Volume:
56, Issue:
19
Journal Article
Peer reviewed
The Nrf2–Keap1 system plays a major role in cellular defense against oxidative stress. Upon exposure to electrophiles, the cysteine-rich protein Keap1 is covalently modified, and it is this ...modification of Keap1 that allows the accumulation and subsequent nuclear translocation of Nrf2 where it induces the transcription of over 100 protective genes. This mechanism can be exploited in drug discovery approaches to diseases such as chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), asthma, and neurodegenerative diseases like multiple sclerosis (MS) and Parkinson’s, utilizing the modification of Keap1 by electrophiles, compounds that would not normally be considered useful in drug discovery programs. This Perspective discusses the development of potential therapies based on potent electrophiles, such as isothiocyanates and Michael acceptors, that, far from being associated with toxic events, can actually initiate a range of beneficial protective pathways.
IMPORTANCE: Mild traumatic brain injury (mTBI), or concussion, in children is a rapidly growing public health concern because epidemiologic data indicate a marked increase in the number of emergency ...department visits for mTBI over the past decade. However, no evidence-based clinical guidelines have been developed to date for diagnosing and managing pediatric mTBI in the United States. OBJECTIVE: To provide a guideline based on a previous systematic review of the literature to obtain and assess evidence toward developing clinical recommendations for health care professionals related to the diagnosis, prognosis, and management/treatment of pediatric mTBI. EVIDENCE REVIEW: The Centers for Disease Control and Prevention (CDC) National Center for Injury Prevention and Control Board of Scientific Counselors, a federal advisory committee, established the Pediatric Mild Traumatic Brain Injury Guideline Workgroup. The workgroup drafted recommendations based on the evidence that was obtained and assessed within the systematic review, as well as related evidence, scientific principles, and expert inference. This information includes selected studies published since the evidence review was conducted that were deemed by the workgroup to be relevant to the recommendations. The dates of the initial literature search were January 1, 1990, to November 30, 2012, and the dates of the updated literature search were December 1, 2012, to July 31, 2015. FINDINGS: The CDC guideline includes 19 sets of recommendations on the diagnosis, prognosis, and management/treatment of pediatric mTBI that were assigned a level of obligation (ie, must, should, or may) based on confidence in the evidence. Recommendations address imaging, symptom scales, cognitive testing, and standardized assessment for diagnosis; history and risk factor assessment, monitoring, and counseling for prognosis; and patient/family education, rest, support, return to school, and symptom management for treatment. CONCLUSIONS AND RELEVANCE: This guideline identifies the best practices for mTBI based on the current evidence; updates should be made as the body of evidence grows. In addition to the development of the guideline, CDC has created user-friendly guideline implementation materials that are concise and actionable. Evaluation of the guideline and implementation materials is crucial in understanding the influence of the recommendations.
IMPORTANCE: In recent years, there has been an exponential increase in the research guiding pediatric mild traumatic brain injury (mTBI) clinical management, in large part because of heightened ...concerns about the consequences of mTBI, also known as concussion, in children. The CDC National Center for Injury Prevention and Control’s (NCIPC) Board of Scientific Counselors (BSC), a federal advisory committee, established the Pediatric Mild TBI Guideline workgroup to complete this systematic review summarizing the first 25 years of literature in this field of study. OBJECTIVE: To conduct a systematic review of the pediatric mTBI literature to serve as the foundation for an evidence-based guideline with clinical recommendations associated with the diagnosis and management of pediatric mTBI. EVIDENCE REVIEW: Using a modified Delphi process, the authors selected 6 clinical questions on diagnosis, prognosis, and management or treatment of pediatric mTBI. Two consecutive searches were conducted on PubMed, Embase, ERIC, CINAHL, and SportDiscus. The first included the dates January 1, 1990, to November 30, 2012, and an updated search included December 1, 2012, to July 31, 2015. The initial search was completed from December 2012 to January 2013; the updated search, from July 2015 to August 2015. Two authors worked in pairs to abstract study characteristics independently for each article selected for inclusion. A third author adjudicated disagreements. The risk of bias in each study was determined using the American Academy of Neurology Classification of Evidence Scheme. Conclusion statements were developed regarding the evidence within each clinical question, and a level of confidence in the evidence was assigned to each conclusion using a modified GRADE methodology. Data analysis was completed from October 2014 to May 2015 for the initial search and from November 2015 to April 2016 for the updated search. FINDINGS: Validated tools are available to assist clinicians in the diagnosis and management of pediatric mTBI. A significant body of research exists to identify features that are associated with more serious TBI-associated intracranial injury, delayed recovery from mTBI, and long-term sequelae. However, high-quality studies of treatments meant to improve mTBI outcomes are currently lacking. CONCLUSIONS AND RELEVANCE: This systematic review was used to develop an evidence-based clinical guideline for the diagnosis and management of pediatric mTBI. While an increasing amount of research provides clinically useful information, this systematic review identified key gaps in diagnosis, prognosis, and management.
Patients with limited English proficiency (LEP) benefit from the appropriate use of medical interpreters. A multidisciplinary quality improvement team sought to improve communication with patients ...with LEP within a pediatric emergency department (ED). Specifically, the team aimed to improve the early identification of patients and caregivers with LEP, the utilization of interpreter services for those identified, and documentation of interpreter use in the patient chart.
Using clinical observations and data review, the project team identified key processes for improvement in the ED workflow and introduced interventions to increase identification of language needs and offer interpreter services. These include a new triage screening question, an icon on the ED track board that communicates language needs to staff, an electronic health record (EHR) alert with information on how to obtain interpreter services, and a new template to prompt correct documentation in the ED provider's note. Outcomes were tracked using statistical process control charts.
All study measures met special cause for improvement during the 6-month study period and have been sustained during surveillance data collection. Identification rates for patients with LEP during triage increased from 60% to 77%. Interpreter utilization increased from 77% to 86%. The documentation of interpreter use increased from 38% to 73%.
Using improvement methods, a multidisciplinary team increased the identification of patients and caregivers with LEP in an ED. Integration of this information into the EHR allowed for the targeted prompting of providers to use interpreter services and to correctly document their use.
ABSTRACTIntranasal medication administration in the emergency care of children has been reported for at least 20 years and is gaining popularity because of ease of administration, rapid onset of ...action, and relatively little pain to the patient. The ability to avoid a needle stick is often attractive to practitioners, in addition to children and their parents. In time-critical situations for which emergent administration of medication is needed, the intranasal route may be associated with more rapid medication administration. This article reviews the use of intranasal medications in the emergency care of children. Particular attention will be paid to anatomy and its impact on drug delivery, pharmacodynamics, medications currently administered by this route, delivery devices available, tips for use, and future directions.
KEAP1 is the key regulator of the NRF2-mediated cytoprotective response, and increasingly recognized as a target for diseases involving oxidative stress. Pharmacological intervention has focused on ...molecules that decrease NRF2-ubiquitination through covalent modification of KEAP1 cysteine residues, but such electrophilic compounds lack selectivity and may be associated with off-target toxicity. We report here the first use of a fragment-based approach to directly target the KEAP1 Kelch–NRF2 interaction. X-ray crystallographic screening identified three distinct “hot-spots” for fragment binding within the NRF2 binding pocket of KEAP1, allowing progression of a weak fragment hit to molecules with nanomolar affinity for KEAP1 while maintaining drug-like properties. This work resulted in a promising lead compound which exhibits tight and selective binding to KEAP1, and activates the NRF2 antioxidant response in cellular and in vivo models, thereby providing a high quality chemical probe to explore the therapeutic potential of disrupting the KEAP1–NRF2 interaction.
Pediatric cardiac arrest in the out-of-hospital setting is a traumatic event for family, friends, caregivers, classmates, and school personnel. Immediate bystander cardiopulmonary resuscitation and ...the use of automatic external defibrillators have been shown to improve survival in adults. There is some evidence to show improved survival in children who receive immediate bystander cardiopulmonary resuscitation. Pediatricians, in their role as advocates to improve the health of all children, are uniquely positioned to strongly encourage the training of children, parents, caregivers, school personnel, and the lay public in the provision of basic life support, including pediatric basic life support, as well as the appropriate use of automated external defibrillators.
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