ITI-D1 Kunitz domain mutants as hNE inhibitors
AssigneeDyax Corp.
InventorsArthur Ley, Sonia Guterman, William Markland, Rachel Kent, Bruce Roberts, Robert Ladner
Life of this patent
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Abstract
Mutants of Kunitz domain 1 (ITI-D1) of human inter-α-trypsin inhibitor (ITI), are useful as inhibitors of human neutrophil elastase. Mutants characterized by one or more of the following substitutions (numbered to correspond to bovine pancreatic trypsin inhibitor, the archetypal Kunitz domain) are of particular interest: (a) Val15 or Ile15, (b) Ala16, (c) Phe18, (d) Pro19, (e) Arg1, (f) Pro2, and/or (g) Phe4.
Claims36
A non-naturally occurring protein which inhibits human neutrophil elastase and which is a protein comprising at least the core sequence of a non-naturally occurring Kunitz domain, said Kunitz domain being more similar in sequence to the core sequence 26-76 of ITI-D1 than to the core sequence 5-55 of BPTI, when its cysteines are aligned with those of BPTI and ITI-D1, but said domain differing from ITI-D1 in that at least one of the following conditions applies:
- (a) the residue corresponding to BPTI residue 15 and ITI-D1 residue M36 is Val or Ile,
- (b) the residue corresponding to BPTI residue 16 and ITI-D1 residue G37 is Ala,
- (c) the residue corresponding to BPTI residue 18 and ITI-D1 residue T39 is Phe,
- (d) the residue corresponding to BPTI residue 19 and ITI-D1 residue S40 is Pro,
- (e) the residue corresponding to BPTI residue 1 and ITI-D1 residue K22, if any, is Arg,
- (f) the residue corresponding to BPTI residue 2 and ITI-D1 residue E23, if any, is Pro, or
- (g) the residue corresponding to BPTI residue 4 and ITI-D1 residue S25, if any, is Phe.
Dependencies are inferred from the claim text.