Compositions and methods for the delivery of nitric oxide
AssigneeThe Regents of the University of California
InventorsSTEPHEN P. L. CARY, ELIZABETH M. BOON, JONATHAN A. WINGER, MICHAEL A. MARLETTA
Life of this patent
Estimating the term…
Abstract
H-NOX proteins are mutated to exhibit improved or optimal kinetic and thermodynamic properties for blood gas NO delivery. The engineered H-NOX proteins comprise mutations that impart altered NO or O2 ligand-binding relative to the corresponding wild-type H-NOX domain, and are operative as physiologically compatible mammalian blood NO gas carriers. The invention also provides pharmaceutical compositions, kits, and methods that use wild-type or mutant H-NOX proteins for the treatment of any condition for which delivery of NO is beneficial.
Claims21
1-320. (canceled)
An isolated H-NOX protein comprising at least one mutation that alters the koff, k1, or k2 for NO, the O2 dissociation constant, the NO dissociation constant, or the NO reactivity compared to that of a corresponding wild type H-NOX protein, wherein the mutant H-NOX protein is not Thermoanaerobacter tengcongensis H-NOX Y140L, T. tengcongensis H-NOX W9F, T. tengcongensis H-NOX F78Y/Y140L, Legionella pneumophilia 2 H-NOX F142Y, Rattus norvegicus sGC β1 H-NOX (1-385) I145Y;
- and wherein either
- (a) the koff, k1, or k2 for NO of the H-NOX protein is between about 1×10−4 s−1 and about 10 s−1 at 37° C., and the O2 dissociation constant of the H-NOX protein is at least about 1 μM at 37° C., or
- (b) the NO dissociation constant of the H-NOX protein is within 2 orders of magnitude of that of human hemoglobin alpha, and the NO reactivity of the H-NOX protein is at least 10-fold lower than that of human hemoglobin alpha.
A method of delivering NO to an individual comprising administering to the individual in need thereof an H-NOX protein in an amount sufficient to deliver an effective amount of NO to an individual, wherein the NO dissociation constant of the H-NOX protein is within 2 orders of magnitude of that of human hemoglobin alpha, and the NO reactivity of the H-NOX protein is at least 10-fold lower than that of human hemoglobin alpha.
Dependencies are inferred from the claim text.