Carlos Batthyány

The emergence of glucagon-like peptide-1 agonists represents a notable advancement in the pharmacological treatment of obesity, yet complementary approaches are essential. Through phenotypic drug discovery, we developed promising nitroalkene-containing small molecules for obesity-related metabolic dysfunctions. Here, we present SANA, a nitroalkene derivative of salicylate, demonstrating notable efficacy in preclinical models of diet-induced obesity. SANA reduces liver steatosis and insulin resistance by enhancing mitochondrial respiration and increasing creatine-dependent energy expenditure in adipose tissue, functioning effectively in thermoneutral conditions and independently of uncoupling protein 1 and AMPK activity. Finally, we conducted a randomized, double-blind, placebo-controlled phase 1A/B clinical trial, which consisted of two parts, each with four arms: (A) single ascending doses (200–800 mg) in healthy lean volunteers; (B) multiple ascending doses (200–400 mg per day for 15 days) in healthy volunteers with overweight or obesity. The primary endpoint assessed safety and tolerability. Secondary and exploratory endpoints included pharmacokinetics, tolerability, body weight and metabolic markers. SANA shows good safety and tolerability, and demonstrates beneficial effects on body weight and glucose management within 2 weeks of treatment. Overall, SANA appears to be a first-in-class activator of creatine-dependent energy expenditure and thermogenesis, highlighting its potential as a therapeutic candidate for ‘diabesity’. Australian New Zealand Clinical Trials Registry registration: ACTRN12622001519741.

Peroxiredoxins are abundant and ubiquitous proteins that participate in different cellular functions, such as oxidant detoxification, protein folding, and intracellular signaling. Under different cellular conditions, peroxiredoxins can be secreted by different parasites, promoting the induction of immune responses in hosts. In this work, we demonstrated that the cytosolic tryparedoxin peroxidase of Trypanosoma cruzi (cTXNPx) is secreted by epimastigotes and trypomastigotes associated with extracellular vesicles and also as a vesicle-free protein. By confocal microscopy, we show that cTXNPx can enter host cells by an active mechanism both through vesicles and as a recombinant protein. Transcriptomic analysis revealed that cTXNPx induces endoplasmic reticulum stress and interleukin-8 expression in epithelial cells. This analysis also suggested alterations in cholesterol metabolism in cTXNPx-treated cells, which was confirmed by immunofluorescence showing the accumulation of LDL and the induction of LDL receptors in both epithelial cells and macrophages. BrdU incorporation assays and qPCR showed that cTXNPx has a mitogenic, proliferative, and proinflammatory effect on these cells in a dose–dependent manner. Importantly, we also demonstrated that cTXNPx acts as a paracrine virulence factor, increasing the susceptibility to infection in cTXNPx-pretreated epithelial cells by approximately 40%. Although the results presented in this work are from in vitro studies and likely underestimate the complexity of parasite–host interactions, our work suggests a relevant role for this protein in establishing infection.

Obesity-related type II diabetes (diabesity) has increased global morbidity and mortality dramatically. Previously, the ancient drug salicylate demonstrated promise for the treatment of type II diabetes, but its clinical use was precluded due to high dose requirements. In this study, we present a nitroalkene derivative of salicylate, 5-(2-nitroethenyl)salicylic acid (SANA), a molecule with unprecedented beneficial effects in diet-induced obesity (DIO). SANA reduces DIO, liver steatosis and insulin resistance at doses up to 40 times lower than salicylate. Mechanistically, SANA stimulated mitochondrial respiration and increased creatine-dependent energy expenditure in adipose tissue. Indeed, depletion of creatine resulted in the loss of SANA action. Moreover, we found that SANA binds to creatine kinases CKMT1/2, and downregulation CKMT1 interferes with the effect of SANA in vivo. Together, these data demonstrate that SANA is a first-in-class activator of creatine-dependent energy expenditure and thermogenesis in adipose tissue and emerges as a candidate for the treatment of diabesity.

Obesity-related type II diabetes (diabesity) has increased global morbidity and mortality dramatically. Previously, the ancient drug salicylate demonstrated promise for the treatment of type II diabetes, but its clinical use was precluded due to high dose requirements and concomitant side effects. Recently, we showed that the nitroalkene group of unsaturated nitro-fatty acids can be attached to different molecular scaffolds to confer beneficial drug actions. In this study, we designed a nitroalkene derivative of salicylate, 5-(2-nitroethenyl)salicylic acid (SANA), and assessed its effects in murine diet-induced obesity (DIO). The data show that SANA reduces DIO, liver steatosis and insulin resistance at doses up to 40 times lower than salicylate. Analyses of adipose tissue revealed SANA-mediated stimulation of mitochondrial respiration, via a creatine-dependent heat production pathway. Indeed, depletion of creatine resulted in the loss of SANA action. Together, these data demonstrate SANA as a candidate for the treatment of diabesity.

Background: South America has become the new epicenter of the COVID-19 pandemic with more than 1.1M reported cases and >50,000 deaths (June 2020). Conversely, Uruguay stands out as an outlier managing this health crisis with remarkable success. Methods: We developed a molecular diagnostic test to detect SARS-CoV-2. This methodology was transferred to research institutes, public hospitals and academic laboratories all around the country, creating a “ COVID-19 diagnostic lab network ”. Uruguay also implemented active epidemiological surveillance following the “Test, Trace and Isolate” (TETRIS) strategy coupled to real-time genomic epidemiology. Results: Three months after the first cases were detected, the number of positive individuals reached 826 (23 deaths, 112 active cases and 691 recovered). The Uruguayan strategy was based in a close synergy established between the national health authorities and the scientific community. In turn, academia rapidly responded to develop national RT-qPCR tests. Consequently, Uruguay was able to perform ∼1,000 molecular tests per day in a matter of weeks. The “ COVID-19 diagnostic lab network ” performed more than 54% of the molecular tests in the country. This, together with real- time genomics, were instrumental to implement the TETRIS strategy, helping to contain domestic transmission of the main outbreaks registered so far. Conclusions: Uruguay has successfully navigated the first trimester of the COVID-19 health crisis in South America. A rapid response by the scientific community to increase testing capacity, together with national health authorities seeking out the support from the academia were fundamental to successfully contain, until now, the COVID-19 outbreak in the country.

Cancer is the second leading cause of death worldwide. Herein, a strategy to quickly and efficiently identify novel lead compounds to develop anticancer agents, using green multicomponent reactions followed by antiproliferative activity and structure–activity relationship studies, is described. A second‐generation focused library of nitric oxide‐releasing compounds was prepared by microwave‐assisted Passerini and Ugi reactions. Nearly all compounds displayed potent antiproliferative activities against a panel of human solid tumor cell lines, with 1‐phenyl‐1‐[(tert‐butylamino)carbonyl]methyl 3‐[(3‐phenylsulfonyl‐[1,2,5]oxadiazol‐4‐yl N²‐oxide)oxy]benzoate (4 k) and N‐[1‐(tert‐butylaminocarbonyl)‐1‐phenylmethyl]‐N‐(4‐methylphenyl)‐3‐(3‐phenylsulfonyl‐[1,2,5]oxadiazol‐4‐yl N²‐oxide)oxyphenyl carboxamide (6 d) exhibiting the strongest activity on SW1573 lung cell line (GI₅₀=110 and 21 nm) with selectivity indices of 70 and 470, respectively. Preliminary mechanistic studies suggest a relationship between NO release and antiproliferative activity. Our strategy allowed the rapid identification of at least two molecules as future candidates for the development of potent antitumor drugs.