Robert J. DeVita
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View article: LRRK2-mediated NLRC4 phosphorylation differentially regulates IL-1β/IL-18 secretion
LRRK2-mediated NLRC4 phosphorylation differentially regulates IL-1β/IL-18 secretion Open
In the present study, we explored the relation of LRRK2-kinase phosphorylation of the NLRC4 inflammasome to NLRC4 inflammasome function in normal humans and mice, as well as in patients with Crohn’s disease (CD). We found that LRRK2-kinase…
View article: Functional genomics pipeline identifies CRL4 inhibition for the treatment of ovarian cancer
Functional genomics pipeline identifies CRL4 inhibition for the treatment of ovarian cancer Open
Background The goal of precision oncology is to find effective therapeutics for every patient. Through the inclusion of emerging therapeutics in a high‐throughput drug screening platform, our functional genomics pipeline inverts the common…
View article: Hippocampal γCaMKII dopaminylation promotes synaptic-to-nuclear signaling and memory formation
Hippocampal γCaMKII dopaminylation promotes synaptic-to-nuclear signaling and memory formation Open
Protein monoaminylation is a class of posttranslational modification (PTM) that contributes to transcription, physiology and behavior. While recent analyses have focused on histones as critical substrates of monoaminylation, the broader re…
View article: A Phase 1 single ascending dose study of pure oral harmine in healthy volunteers
A Phase 1 single ascending dose study of pure oral harmine in healthy volunteers Open
Background: Harmine is a component of the hallucinogenic brew, Ayahuasca, which also contains the psychoactive compound, N, N-dimethyltryptamine. Whether pharmaceutical-grade harmine hydrochloride (HCl) has psychoactive effects, the doses …
View article: Characterization, Structure, and Inhibition of the Human Succinyl-CoA:glutarate-CoA Transferase, a Putative Genetic Modifier of Glutaric Aciduria Type 1
Characterization, Structure, and Inhibition of the Human Succinyl-CoA:glutarate-CoA Transferase, a Putative Genetic Modifier of Glutaric Aciduria Type 1 Open
Glutaric Aciduria Type 1 (GA1) is a serious inborn error of metabolism with no pharmacological treatments. A novel strategy to treat this disease is to divert the toxic biochemical intermediates to less toxic or nontoxic metabolites. Here,…
View article: Select DYRK1A Inhibitors Enhance Both Proliferation and Differentiation in Human Pancreatic Beta Cells
Select DYRK1A Inhibitors Enhance Both Proliferation and Differentiation in Human Pancreatic Beta Cells Open
The small molecule DYRK1A inhibitor, harmine, induces human beta cell proliferation, expands beta cell mass, enhances expression of beta cell phenotypic genes, and improves human beta cell function i n vitro and in vivo . It is unknown whe…
View article: Characterization, structure and inhibition of the human succinyl-CoA:glutarate-CoA transferase, a genetic modifier of glutaric aciduria type 1
Characterization, structure and inhibition of the human succinyl-CoA:glutarate-CoA transferase, a genetic modifier of glutaric aciduria type 1 Open
Glutaric Aciduria Type 1 (GA1) is a serious inborn error of metabolism with no pharmacological treatments. A novel strategy to treat this disease is to divert the toxic biochemical intermediates to less toxic or non-toxic metabolites. Here…
View article: A case of hyperlysinemia identified by urine newborn screening
A case of hyperlysinemia identified by urine newborn screening Open
Hyperlysinemia is a rare autosomal recessive deficiency of 2‐aminoadipic semialdehyde synthase (AASS) affecting the initial step in lysine degradation. It is thought to be a benign biochemical abnormality, but reports on cases remain scarc…
View article: <scp>Acyl‐CoA</scp> dehydrogenase substrate promiscuity: Challenges and opportunities for development of substrate reduction therapy in disorders of valine and isoleucine metabolism
<span>Acyl‐CoA</span> dehydrogenase substrate promiscuity: Challenges and opportunities for development of substrate reduction therapy in disorders of valine and isoleucine metabolism Open
Toxicity of accumulating substrates is a significant problem in several disorders of valine and isoleucine degradation notably short‐chain enoyl‐CoA hydratase (ECHS1 or crotonase) deficiency, 3‐hydroxyisobutyryl‐CoA hydrolase (HIBCH) defic…
View article: Inhibition of LRRK2 Kinase Activity with a Novel Inhibitor (CS 82) Inhibits NLRC4 Inflammasome Activation and Reduces Intestinal Inflammation Severity
Inhibition of LRRK2 Kinase Activity with a Novel Inhibitor (CS 82) Inhibits NLRC4 Inflammasome Activation and Reduces Intestinal Inflammation Severity Open
In the last twenty years Leucine Rich Repeat Kinase 2 (LRRK2) has received immense attention due to its association with several diseases, for example, neurodegenerative disease PD (Parkinson’s Disease), inflammatory bowel disease (IBD), C…
View article: Acyl-CoA dehydrogenase substrate promiscuity limits the potential for development of substrate reduction therapy in disorders of valine and isoleucine metabolism
Acyl-CoA dehydrogenase substrate promiscuity limits the potential for development of substrate reduction therapy in disorders of valine and isoleucine metabolism Open
Toxicity of accumulating substrates is a significant problem in several disorders of valine and isoleucine degradation notably short-chain enoyl-CoA hydratase (ECHS1 or crotonase) deficiency, 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) defic…
View article: Characterization and structure of the human lysine-2-oxoglutarate reductase domain, a novel therapeutic target for treatment of glutaric aciduria type 1
Characterization and structure of the human lysine-2-oxoglutarate reductase domain, a novel therapeutic target for treatment of glutaric aciduria type 1 Open
In humans, a single enzyme 2-aminoadipic semialdehyde synthase (AASS) catalyses the initial two critical reactions in the lysine degradation pathway. This enzyme evolved to be a bifunctional enzyme with both lysine-2-oxoglutarate reductase…
View article: Characterization and structure of the human lysine-2-oxoglutarate reductase domain, a novel therapeutic target for treatment of glutaric aciduria type 1
Characterization and structure of the human lysine-2-oxoglutarate reductase domain, a novel therapeutic target for treatment of glutaric aciduria type 1 Open
In humans, a single enzyme 2-aminoadipic semialdehyde synthase (AASS) catalyzes the initial two critical reactions in the lysine degradation pathway. This enzyme evolved to be a bifunctional enzyme with both lysine 2-oxoglutarate reductase…
View article: Table S2 from Characterization and structure of the human lysine-2-oxoglutarate reductase domain, a novel therapeutic target for treatment of glutaric aciduria type 1
Table S2 from Characterization and structure of the human lysine-2-oxoglutarate reductase domain, a novel therapeutic target for treatment of glutaric aciduria type 1 Open
Virtual screening compounds and SAR
View article: Small-molecule antagonism of the interaction of the RAGE cytoplasmic domain with DIAPH1 reduces diabetic complications in mice
Small-molecule antagonism of the interaction of the RAGE cytoplasmic domain with DIAPH1 reduces diabetic complications in mice Open
Small-molecule antagonism of RAGE-DIAPH1 reduces diabetes-related complications in mice.
View article: Targeting Cullin-RING E3 Ubiquitin Ligase 4 by Small Molecule Modulators
Targeting Cullin-RING E3 Ubiquitin Ligase 4 by Small Molecule Modulators Open
Cullin-RING E3 ubiquitin ligase 4 (CRL4) plays an essential role in cell cycle progression. Recent efforts using high throughput screening and follow up hit-to-lead studies have led to identification of small molecules 33-11 and KH-4-43 th…
View article: Human Beta Cell Regenerative Drug Therapy for Diabetes: Past Achievements and Future Challenges
Human Beta Cell Regenerative Drug Therapy for Diabetes: Past Achievements and Future Challenges Open
A quantitative deficiency of normally functioning insulin-producing pancreatic beta cells is a major contributor to all common forms of diabetes. This is the underlying premise for attempts to replace beta cells in people with diabetes by …
View article: DYRK1A Inhibitors as Potential Therapeutics for β-Cell Regeneration for Diabetes
DYRK1A Inhibitors as Potential Therapeutics for β-Cell Regeneration for Diabetes Open
According to the World Health Organization (WHO), 422 million people are suffering from diabetes worldwide. Current diabetes therapies are focused on optimizing blood glucose control to prevent long-term diabetes complications. Unfortunate…
View article: Inhibitors of cullin-RING E3 ubiquitin ligase 4 with antitumor potential
Inhibitors of cullin-RING E3 ubiquitin ligase 4 with antitumor potential Open
Significance Cullin-RING E3 ubiquitin ligases (CRLs) direct protein degradation to impact a myriad of physiological and pathological processes including cancer. This work reports the small-molecule compounds 33-11 and KH-4-43 as inhibitors…
View article: Human Beta Cell Mass Expansion In Vivo With A Harmine and Exendin-4 Combination: Quantification and Visualization By iDISCO+ 3D Imaging
Human Beta Cell Mass Expansion In Vivo With A Harmine and Exendin-4 Combination: Quantification and Visualization By iDISCO+ 3D Imaging Open
463 million people globally suffer from diabetes. The majority are deficient in insulin-producing pancreatic beta cells, although beta cells remain in most people with diabetes. Unfortunately, although many diabetes drugs exist, none is ab…
View article: Inhibition and Crystal Structure of the Human DHTKD1-Thiamin Diphosphate Complex
Inhibition and Crystal Structure of the Human DHTKD1-Thiamin Diphosphate Complex Open
DHTKD1 is the E1 component of the 2-oxoadipate dehydrogenase complex, which is an enzyme involved in the catabolism of (hydroxy-)lysine and tryptophan. Mutations in DHTKD1 have been associated with 2-aminoadipic and 2-oxoadipic aciduria, C…
View article: Structure–Activity Relationships and Biological Evaluation of 7-Substituted Harmine Analogs for Human β-Cell Proliferation
Structure–Activity Relationships and Biological Evaluation of 7-Substituted Harmine Analogs for Human β-Cell Proliferation Open
Recently, we have shown that harmine induces β-cell proliferation both in vitro and in vivo, mediated via the DYRK1A-NFAT pathway. We explore structure–activity relationships of the 7-position of harmine for both DYRK1A kinase inhibition a…
View article: DHTKD1 and OGDH display substrate overlap in cultured cells and form a hybrid 2-oxo acid dehydrogenase complex in vivo
DHTKD1 and OGDH display substrate overlap in cultured cells and form a hybrid 2-oxo acid dehydrogenase complex in vivo Open
Glutaric aciduria type 1 (GA1) is an inborn error of lysine degradation characterized by a specific encephalopathy that is caused by toxic accumulation of lysine degradation intermediates. Substrate reduction through inhibition of DHTKD1, …
View article: GLP-1 receptor agonists synergize with DYRK1A inhibitors to potentiate functional human β cell regeneration
GLP-1 receptor agonists synergize with DYRK1A inhibitors to potentiate functional human β cell regeneration Open
GLP-1 receptor agonists, widely used to treat diabetes, are converted to human β cell regenerative drugs by adding a DYRK1A inhibitor.
View article: Synthesis and Biological Validation of a Harmine-Based, Central Nervous System (CNS)-Avoidant, Selective, Human β-Cell Regenerative Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase A (DYRK1A) Inhibitor
Synthesis and Biological Validation of a Harmine-Based, Central Nervous System (CNS)-Avoidant, Selective, Human β-Cell Regenerative Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase A (DYRK1A) Inhibitor Open
Recently, our group identified that harmine is able to induce β-cell proliferation both in vitro and in vivo, mediated via the DYRK1A-NFAT pathway. Since, harmine suffers from a lack of selectivity, both against other kinases and CNS off-t…
View article: Inhibition and Crystal Structure of the Human DHTKD1-Thiamin Diphosphate Complex
Inhibition and Crystal Structure of the Human DHTKD1-Thiamin Diphosphate Complex Open
DHTKD1 is the E1 component of the 2-oxoadipic acid dehydrogenase complex (OADHc), which functions in the L-lysine degradation pathway. Mutations in DHTKD1 have been associated with 2-aminoadipic and 2-oxoadipic aciduria, Charcot-Marie-Toot…