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1.
Int J Mol Sci ; 23(20)2022 Oct 14.
Article in English | MEDLINE | ID: covidwho-2071511

ABSTRACT

Caloric restriction promotes longevity in multiple animal models. Compounds modulating nutrient-sensing pathways have been suggested to reproduce part of the beneficial effect of caloric restriction on aging. However, none of the commonly studied caloric restriction mimetics actually produce a decrease in calories. Sodium-glucose cotransporter 2 inhibitors (SGLT2-i) are a class of drugs which lower glucose by promoting its elimination through urine, thus inducing a net loss of calories. This effect promotes a metabolic shift at the systemic level, fostering ketones and fatty acids utilization as glucose-alternative substrates, and is accompanied by a modulation of major nutrient-sensing pathways held to drive aging, e.g., mTOR and the inflammasome, overall resembling major features of caloric restriction. In addition, preliminary experimental data suggest that SGLT-2i might also have intrinsic activities independent of their systemic effects, such as the inhibition of cellular senescence. Consistently, evidence from both preclinical and clinical studies have also suggested a marked ability of SGLT-2i to ameliorate low-grade inflammation in humans, a relevant driver of aging commonly referred to as inflammaging. Considering also the amount of data from clinical trials, observational studies, and meta-analyses suggesting a tangible effect on age-related outcomes, such as cardiovascular diseases, heart failure, kidney disease, and all-cause mortality also in patients without diabetes, here we propose a framework where at least part of the benefit provided by SGLT-2i is mediated by their ability to blunt the drivers of aging. To support this postulate, we synthesize available data relative to the effect of this class on: 1- animal models of healthspan and lifespan; 2- selected molecular pillars of aging in preclinical models; 3- biomarkers of aging and especially inflammaging in humans; and 4- COVID-19-related outcomes. The burden of evidence might prompt the design of studies testing the potential employment of this class as anti-aging drugs.


Subject(s)
COVID-19 , Diabetes Mellitus, Type 2 , Sodium-Glucose Transporter 2 Inhibitors , Animals , Humans , Sodium-Glucose Transporter 2 Inhibitors/pharmacology , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Sodium-Glucose Transporter 2 , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Inflammasomes , Drug Repositioning , Diabetes Mellitus, Type 2/drug therapy , Aging , Glucose/therapeutic use , TOR Serine-Threonine Kinases , Sodium , Ketones/therapeutic use , Fatty Acids/therapeutic use
2.
Angew Chem Int Ed Engl ; 60(49): 25933-25941, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1439669

ABSTRACT

We present the results of classical and QM/MM simulations for the inhibition of SARS-CoV-2 3CL protease by a hydroxymethylketone inhibitor, PF-00835231. In the noncovalent complex the carbonyl oxygen atom of the warhead is placed in the oxyanion hole formed by residues 143 to 145, while P1-P3 groups are accommodated in the active site with interactions similar to those observed for the peptide substrate. According to alchemical free energy calculations, the P1' hydroxymethyl group also contributes to the binding free energy. Covalent inhibition of the enzyme is triggered by the proton transfer from Cys145 to His41. This step is followed by the nucleophilic attack of the Sγ atom on the carbonyl carbon atom of the inhibitor and a proton transfer from His41 to the carbonyl oxygen atom mediated by the P1' hydroxyl group. Computational simulations show that the addition of a chloromethyl substituent to the P1' group may lower the activation free energy for covalent inhibition.


Subject(s)
Coronavirus 3C Proteases/antagonists & inhibitors , Drug Design , Ketones/chemistry , Protease Inhibitors/chemistry , SARS-CoV-2/enzymology , Binding Sites , COVID-19/drug therapy , COVID-19/virology , Catalytic Domain , Coronavirus 3C Proteases/metabolism , Humans , Ketones/metabolism , Ketones/therapeutic use , Kinetics , Molecular Dynamics Simulation , Protease Inhibitors/metabolism , Protease Inhibitors/therapeutic use , SARS-CoV-2/isolation & purification , Thermodynamics
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