Compositions and methods for the delivery of oxygen
AssigneeThe Regents of the University of California
InventorsStephen P. L. Cary, Elizabeth M. Boon, Emily Weinert, Jonathan A. Winger, Michael A. Marletta
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Abstract
H—NOX proteins are mutated to exhibit improved or optimal kinetic and thermodynamic properties for blood gas O2 delivery. The engineered H—NOX proteins comprise mutations that impart altered O2 or NO ligand-binding relative to the corresponding wild-type H—NOX domain, and are operative as physiologically compatible mammalian blood O2 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 O2 is beneficial.
Claims26
An isolated nucleic acid encoding a mutant H—NOX protein, wherein the mutant H—NOX protein comprises at least one distal pocket mutation that alters the 02 dissociation constant or NO reactivity compared to that of a corresponding wild-type H—NOX protein, wherein the 02 dissociation constant of the mutant H—NOX protein is within 2 orders of magnitude of that of hemoglobin, wherein the NO reactivity of the mutant H—NOX protein is at least 10-fold lower than that of hemoglobin,
- wherein the distal pocket mutation comprises a substitution at a residue that corresponds to at least one of Thr4, Ile5, Thr8, Trp9, Trp67, Asn74, Ile75, Phe78, Phe82, Tyr140, and Leu144 of a T. tengcongensis H—NOX protein of SEQ ID NO:
- 54,
- and wherein the mutant H—NOX protein is not T. tengcongensis H—NOX Y140L, T. tengcongensis H—NOX F78Y/Y140L, T. tengcongensis H—NOX W9F, T. tengcongensis H—NOX W9F/Y140L, H. sapiens β1 H—NOX (1-385) I145Y, or L. pneumophilia 2 H—NOX F142Y.
An isolated nucleic acid encoding a mutant H—NOX protein comprising a distal pocket mutation wherein the 02 dissociation constant of the mutant H—NOX protein is within 2 orders of magnitude of that of hemoglobin, wherein the NO reactivity of the mutant H—NOX protein is at least 10-fold lower than that of hemoglobin, and wherein the distal pocket mutation is at an amino acid position corresponding to position 144 of T. tengcongensis H—NOX protein of SEQ ID NO:54.
An isolated nucleic acid encoding a mutant H—NOX protein comprising a distal pocket mutation, wherein the 02 dissociation constant of the mutant H—NOX protein is within 2 orders of magnitude of that of hemoglobin, wherein the NO reactivity of the mutant H—NOX protein is at least 10-fold lower than that of hemoglobin,
- wherein the mutant H—NOX protein is a T. tengcongensis H—NOX protein comprising a L144F mutation in SEQ ID NO:
- 54,
- wherein the mutant H—NOX protein is a fusion protein that includes an H—NOX domain and part or all of another protein.
Dependencies are inferred from the claim text.