Herbacetin

25001863

Mechanism-based sepsis treatments are unavailable, and their incidence is rising worldwide. Deaths occur during the early acute phase of hyperinflammation or subsequent postacute hypoinflammatory phase with sustained organ failure. The acute sepsis phase shifts rapidly, and multiple attempts to treat early excessive inflammation have uniformly failed. We reported in a sepsis cell model and human sepsis blood leukocytes that nuclear NAD+ sensor SIRT1 deacetylase remodels chromatin at specific gene sets to switch the acute-phase proinflammatory response to hypoinflammatory. Importantly, SIRT1 chromatin reprogramming is reversible, suggesting that inhibition of SIRT1 might reverse postacute-phase hypoinflammation. We tested this concept in septic mice, using the highly specific SIRT1 inhibitor EX-527, a small molecule that closes the NAD+ binding site of SIRT1. Strikingly, when administered 24 h after sepsis, all treated animals survived, whereas only 40% of untreated mice survived. EX-527 treatment reversed the inability of leukocytes to adhere at the small intestine MVI, reversed in vivo endotoxin tolerance, increased leukocyte accumulation in peritoneum, and improved peritoneal bacterial clearance. Mechanistically, the SIRT1 inhibitor restored repressed endothelial E-selectin and ICAM-1 expression and PSGL-1 expression on the neutrophils. Systemic benefits of EX-527 treatment included stabilized blood pressure, improved microvascular blood flow, and a shift toward proimmune macrophages in spleen and bone marrow. Our findings reveal that modifying the SIRT1 NAD+ axis may provide a novel way to treat sepsis in its hypoinflammatory phase.

immunosuppression, chromatin remodeling, endotoxin tolerance

SIRT1 inhibition during the hypoinflammatory phenotype of sepsis enhances immunity and improves outcome

Vidula T. Vachharajani,*,1 Tiefu Liu,† Candice M. Brown,† Xianfeng Wang,* Nancy L. Buechler,* Jonathan David Wells,‡ Barbara K. Yoza,†‡ and Charles E. McCall†

2014 Nov

31570394

AT-527 is a novel modified guanosine nucleotide prodrug inhibitor of the hepatitis C virus (HCV) NS5B polymerase, with increased in vitro antiviral activity compared to sofosbuvir and a highly differentiated favorable preclinical profile compared to other anti-HCV nucleoside/nucleotide analogs. This was a multiple-part clinical study where multiple ascending doses of AT-527 up to 600 mg (expressed as AT-527 salt form; equivalent to 553 mg free base) once daily for 7 days were evaluated in a randomized, double-blind, placebo-controlled study of treatment-naive, noncirrhotic, genotype 1b, HCV-infected subjects. The highest dose of AT-527 for the same duration was then evaluated in two open-label cohorts of (i) noncirrhotic, genotype 3, HCV-infected subjects and (ii) HCV-infected subjects of any genotype with compensated (Child-Pugh A) cirrhosis. AT-527 was well tolerated for 7 days in all cohorts. At the highest dose tested, mean HCV RNA reductions of up to 2.4 log10 IU/ml occurred within the first 24 h of dosing. Mean maximum reductions observed with 7 days of dosing were 4.4, 4.5, and 4.6 log10 IU/ml in noncirrhotic subjects with HCV genotype 1b, noncirrhotic subjects with HCV genotype 3, and subjects with compensated cirrhosis, respectively. The systemic half-life of AT-273, the nucleoside metabolite considered a surrogate of intracellular phosphates including the active triphosphate, exceeded 20 h, supporting once-daily dosing. In summary, AT-527 demonstrated rapid, potent, dose/exposure-related, and pangenotypic antiviral activity with similar responses between subjects with and without cirrhosis. Exposure-antiviral response analysis identified 550 mg (free base equivalent) as the optimal dose of AT-527. Safety and antiviral activity data from this study warrant continued clinical development of AT-527 dosed once daily. (This study has been registered in the European Union Drug Regulating Authorities Clinical Trials Database [EudraCT] under number 2017-002148-34 and at ClinicalTrials.gov under identifier NCT03219957.)

chronic hepatitis C virus infection, pangenotypic, direct-acting antiviral, NS5B, nucleotide, cirrhosis

Safety, Pharmacokinetics, and Antiviral Activity of AT-527, a Novel Purine Nucleotide Prodrug, in Hepatitis C Virus-Infected Subjects with or without Cirrhosis

Elina Berliba,corresponding authora Maxim Bogus,a Frederic Vanhoutte,b Pieter-Jan Berghmans,b Steven S. Good,c Adel Moussa,c Keith Pietropaolo,c Robert L. Murphy,c,d Xiao-Jian Zhou,c and Jean-Pierre Sommadossic

2019 Dec