Given the fact that the forecasts show the continuation of the occurrence of cases of coronavirus disease 19 (COVID-19) and the evolution towards Long COVID, the identification of a chemoprophylactic agent is of major importance.For this purpose, we propose SLU-PP-332, an estrogen-related receptor alpha (ERRα) agonist, which, besides the effect of stimulating mitochondrial biogenesis, it is possible to inhibit angiotensin-converting enzyme 2 (ACE2), stimulate immunity, inhibit pro-inflammatory cytokines, reduce the number of entry points into cells of SARS-CoV-2 at the level of adipose tissue through fibronectin type III domain-containing protein 5 (FNDC5), and to protect vascular endothelium from oxidative stress.Considering the existence of exptl. models for COVID-19, it is possible to test these effects, as well as the possibility of combining the administration of SLU-PP-332 with the performance of moderate-intensity phys. exercises, this in order to accelerate the adaptation to exercise of the mitochondria of the whole body, a supposed prophylactic factor for severe forms of COVID-19.

01 Feb 2024·The Journal of Pharmacology and Experimental Therapeutics

A Synthetic ERR Agonist Alleviates Metabolic Syndrome

Article

Author: Chatterjee, Arindam ; Avdagic, Amer ; Burris, Thomas P ; Billon, Cyrielle ; Elgendy, Bahaa ; Butler, Andrew A ; Walker, John K ; Schoepke, Emmalie

Physical exercise induces physiologic adaptations and is effective at reducing the risk of premature death from all causes. Pharmacological exercise mimetics may be effective in the treatment of a range of diseases including obesity and metabolic syndrome. Previously, we described the development of SLU-PP-332, an agonist for the estrogen-related receptor (ERR)α, β, and γ nuclear receptors that activates an acute aerobic exercise program. Here we examine the effects of this exercise mimetic in mouse models of obesity and metabolic syndrome. Diet-induced obese or ob/ob mice were administered SLU-PP-332, and the effects on a range of metabolic parameters were assessed. SLU-PP-332 administration mimics exercise-induced benefits on whole-body metabolism in mice including increased energy expenditure and fatty acid oxidation. These effects were accompanied by decreased fat mass accumulation. Additionally, the ERR agonist effectively reduced obesity and improved insulin sensitivity in models of metabolic syndrome. Pharmacological activation of ERR may be an effective method to treat metabolic syndrome and obesity. SIGNIFICANCE STATEMENT: An estrogen receptor-related orphan receptor agonist, SLU-PP-332, with exercise mimetic activity, holds promise as a therapeutic to treat metabolic diseases by decreasing fat mass in mouse models of obesity.

16 Jan 2024·Circulation

Novel Pan-ERR Agonists Ameliorate Heart Failure Through Enhancing Cardiac Fatty Acid Metabolism and Mitochondrial Function

Article

Author: Qi, Lei ; Hong, Seok Jae ; Zhang, Lilei ; Jensen, Brian C. ; Wilderman, Andrea ; Rideb, Jernie Rae Dela Cruz ; Hayes, Matthew ; Downes, Michael ; Hampton, Carissa S. ; Adeyemi, Christiana M. ; Evans, Ronald M. ; Losby, McKenna ; Fu, Chen ; Nasiotis, Eleni ; Graves, Andrea ; Welch, Ryan D. ; Xu, Weiyi ; Fan, Weiwei ; Yu, Keyang ; Li, Hui ; Walker, John K. ; Zhao, Yuanbiao ; Pei, Liming ; Milosavljevic, Aleksandar ; Billon, Cyrielle ; Oh, Tae Gyu ; Burris, Thomas

BACKGROUND:Cardiac metabolic dysfunction is a hallmark of heart failure (HF). Estrogen-related receptors ERRα and ERRγ are essential regulators of cardiac metabolism. Therefore, activation of ERR could be a potential therapeutic intervention for HF. However, in vivo studies demonstrating the potential usefulness of ERR agonist for HF treatment are lacking, because compounds with pharmacokinetics appropriate for in vivo use have not been available.METHODS:Using a structure-based design approach, we designed and synthesized 2 structurally distinct pan-ERR agonists, SLU-PP-332 and SLU-PP-915. We investigated the effect of ERR agonist on cardiac function in a pressure overload–induced HF model in vivo. We conducted comprehensive functional, multi-omics (RNA sequencing and metabolomics studies), and genetic dependency studies both in vivo and in vitro to dissect the molecular mechanism, ERR isoform dependency, and target specificity.RESULTS:Both SLU-PP-332 and SLU-PP-915 significantly improved ejection fraction, ameliorated fibrosis, and increased survival associated with pressure overload–induced HF without affecting cardiac hypertrophy. A broad spectrum of metabolic genes was transcriptionally activated by ERR agonists, particularly genes involved in fatty acid metabolism and mitochondrial function. Metabolomics analysis showed substantial normalization of metabolic profiles in fatty acid/lipid and tricarboxylic acid/oxidative phosphorylation metabolites in the mouse heart with 6-week pressure overload. ERR agonists increase mitochondria oxidative capacity and fatty acid use in vitro and in vivo. Using both in vitro and in vivo genetic dependency experiments, we show that ERRγ is the main mediator of ERR agonism-induced transcriptional regulation and cardioprotection and definitively demonstrated target specificity. ERR agonism also led to downregulation of cell cycle and development pathways, which was partially mediated by E2F1 in cardiomyocytes.CONCLUSIONS:ERR agonists maintain oxidative metabolism, which confers cardiac protection against pressure overload–induced HF in vivo. Our results provide direct pharmacologic evidence supporting the further development of ERR agonists as novel HF therapeutics.

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Indication	Highest Phase	Country/Location	Organization	Date
Metabolic Syndrome	Preclinical	United States	Washington University School of Medicine	22 Sep 2023
Metabolic Diseases	Preclinical	-	St. Louis College of Pharmacy	29 Mar 2023

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