A Peptidyl Inhibitor that Blocks Calcineurin–NFAT Interaction and Prevents Acute Lung Injury

Abstract

Acute respiratory distress syndrome (ARDS) is an inflammatory lung disease with a high morbidity and mortality rate, for which no pharmacologic treatment is currently available. Our previous studies discovered that a pivotal step in the disease process is the activation of the nuclear factor of activated T cells (NFAT) c3 in lung macrophages, suggesting that inhibitors against the upstream protein phosphatase calcineurin should be effective for prevention/treatment of ARDS. Herein, we report the development of a highly potent, cell-permeable, and metabolically stable peptidyl inhibitor, CNI103, which selectively blocks the interaction between calcineurin and NFATc3, through computational and medicinal chemistry. CNI103 specifically inhibited calcineurin signaling in vitro and in vivo and exhibited a favorable pharmacokinetic profile, broad tissue distribution following different routes of administration, and minimal toxicity. Our data indicate that CNI103 is a promising novel treatment for ARDS and other inflammatory diseases.

Targeting Colorectal Cancer with Conjugates of a Glucose Transporter Inhibitor and 5-Fluorouracil

“…The concentration of compound 7 dropped rapidly in 10 min (Figure a), presumably related to the expression of carboxylesterase and dihydropyrimidine dehydrogenase (DPD) and the high tissue penetration of 7 in mouse blood. − 5-FU released from compound 7 was detected within 2 h and persisted in blood longer than compound 7 (Figure a). Compound 7 exhibited an unusual plasma pharmacokinetic (PK) profile in that its concentration was undetectable (lower detection limit = 0.003 μg/mL) after 30 min but detectable again after 45 min and 4 h, suggesting it to be rapidly absorbed by mouse cells and tissues and reach an equilibrium during elimination . To investigate the distribution-related antitumor efficacy of compound 7 , blood samples were collected after intraperitoneal injection (i.p.)…”

“…Compound 7 exhibited an unusual plasma pharmacokinetic (PK) profile in that its concentration was undetectable (lower detection limit = 0.003 μg/mL) after 30 min but detectable again after 45 min and 4 h, suggesting it to be rapidly absorbed by mouse cells and tissues and reach an equilibrium during elimination. 46 To investigate the distribution-related antitumor efficacy of compound 7, blood samples were collected after intraperitoneal injection (i.p.) (50 mg/kg) of compound 7 and 5-FU in BALB/c mice (n = 3).…”

Can Acute Respiratory Distress Syndrome Be Treated?

“…We have recently developed a selective peptidyl inhibitor of the calcineurin-NFAT interaction, CNI103. CNI103 blocked NFATc3 activation in lung macrophages, decreased the production of TNF-α and IL-6, and prevented the development of sepsis-induced acute lung injury/ARDS in a mouse model [20]. In vitro/ex vivo studies demonstrate that CNI103 readily enters macrophages, monocytes and neutrophils but less efficiently T or B cells, suggesting that CNI103 may attenuate the inflammatory responses to viral infection without blocking T-and B-cell-mediated viral clearance.…”

Discovery of Highly Selective and Orally Bioavailable PI3Kδ Inhibitors with Anti-Inflammatory Activity for Treatment of Acute Lung Injury

“…15 Meanwhile, a peptidyl inhibitor to block calcineurin−NFAT interaction and prevent ALI was developed. 16 Besides, cyclotheonellazole A was disclosed as an elastase inhibitor for alleviating ALI with reductions in lung edema and pathological deterioration. 17 Phosphatidylinositol-3-kinase δ (PI3Kδ) is a subtype of the class I PI3K family and has become a popular therapeutic target in drug discovery.…”