43 - Clinical Evaluation of the Safety and Therapeutic Potential of the Electrophilic Fatty Acid Nitroalkene 10-nitro-octadec-9-enoic acid (10-NO2-OA)

Abstract

The post-translational modification (PTM) of significantly expands the functional proteome. Reactions of nitric oxide (NO) and nitrite (NO2‒) yield products such as nitrogen dioxide (•NO2) that nitrates lipids. Electrophilic fatty acid nitroalkenes (NO2-FA) induce PTM by reversible Michael addition with protein thiols. Multiple transcriptional regulatory proteins contain hyper-reactive functionally-significant nucleophilic amino acids, giving cells a capability for oxidative stress-related adaptive signaling responses. 10-NO2-OA, a synthetic homolog of a species found endogenously, mediates adaptive signaling responses. Human Phase 1 trials of oral and IV formulations of 10-NO2-OA are now revealing the human pharmacology of 10-NO2-OA. Obese (BMI 27-39.5 kg/m2) males were recruited as a surrogate population expressing metabolic and inflammatory stress conditions. Subjects (n=13) received oral 10-NO2-OA (25, 150 or 450 mg) or placebo once daily for 14 d and were fed a uniform diet to limit biomarker and BMI variability. Separately, normal BMI volunteers received 0.34 or 0.68 mg/kg IV 10-NO2-OA. Decreased serum NF-κB-regulated cytokines [leptin, monocyte chemoattractant protein (MCP-1) and Interleukin-6], serum triglycerides and serum cholesterol levels were observed in the high BMI cohort. Increased gene expression of NQO1, HO-1, and HSPA1A/B was observed in PBMNCs (NQO1, HO-1) and urinary exosomes (NQO1, HO-1, HSPA1A/B) in the IV drug-treated group. These responses affirmed that the NFkB, Keap1/Nrf2 and HSF-1 pathway engagement by 10-NO2-OA, observed in preclinical models, is recapitulated in humans. The oral and IV administration of 10-NO2-OA was safe, tolerated and bioavailable.