Pre-Clinical Studies of the NO Scavenger Cobinamide

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DESCRIPTION (provided by applicant): Septic shock, as well as other forms of shock, have extremely high mortality rates, and this, in part, is secondary to the severe hypotension that characterize these clinical states. Nitric oxide (NO) is an extremely potent vasodilator, and its overproduction in shock by inducible NO synthase (NOS) clearly contributes to the vasopressor-refractory hypotension of shock. Non- selective inhibitors of the three mammalian NOS enzymes showed some success in animal models of sepsis, but unfortunately one of these agents led to increased mortality in a Phase III Clinical Trial, possibly secondary to decreased tissue and organ perfusion from inhibition of endothelial NOS. NO scavengers have a theoretical advantage over NOS inhibitors in reducing high NO concentrations in shock, since the former compounds should preferentially neutralize excess circulating NO, without significantly affecting intra- and inter-cellular NO signaling. Indeed, three different NO scavengers, hemoglobin, NOX-100, and cobalamin (vitamin B12) have all shown promise in animal models of sepsis, and NOX-100 has been beneficial in early human clinical trials of septic shock. We have found that cobinamide, the penultimate precursor in the biosynthesis of cobalamin and a contaminant of most vitamin B12 preparations, binds NO with >100 times more affinity than cobalamin. In cultured mammalian cells and in Drosophila Malpighian tubules, cobinamide was an effective NO scavenger, and did not exhibit toxicity at concentrations that would be required to treat states of excess NO. Using a well-established Drosophila model of bacterial sepsis, we have found that cobinamide strikingly increased fly survival, and the mechanism appeared to be from scavenging excess NO. In this R21 application, we propose to perform pre-clinical animal studies to determine if cobinamide is a potentially useful drug candidate; the results of this work will form the basis for an Investigator's New Drug application in anticipation of conducting clinical trials.