TrkAd5: A novel therapeutic agent for treatment of inflammatory pain and asthma.
Elevated levels of nerve growth factor have been linked to the onset and persistence of many pain-related disorders and asthma. Described here are the design, expression, refolding, and purification of a monomeric (nonstrand-swapped) form of the binding domain of the nerve growth factor receptor, designated TrkAd5. We have shown that TrkAd5 produced recombinantly binds nerve growth factor with picomolar affinity. TrkAd5 has been characterized using a variety of biophysical and biochemical assays and is shown here to be stable in both plasma and urine. The palliative effects of TrkAd5 are demonstrated in animal models of inflammatory pain and allergic asthma. We conclude that TrkAd5 will prove effective in ameliorating both acute and chronic conditions where nerve growth factor acts as a mediator and suggest a role for its application in vivo as a novel therapeutic.
Watson
Judy J
JJ
Molecular Neurobiology Unit, Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, Bristol, UK.
Fahey
Mark S
MS
van den Worm
Edwin
E
Engels
Ferdi
F
Nijkamp
Frans P
FP
Stroemer
Paul
P
McMahon
Steve
S
Allen
Shelley J
SJ
Dawbarn
David
D
D000595:Amino Acid Sequence; D000818:Animals; D001249:Asthma / Q000188:drug therapy*; D001665:Binding Sites; D003556:Cystitis / Q000188:drug therapy*; D004355:Drug Stability; D005260:Female; D005612:Freeze Drying; D006168:Guinea Pigs; D008297:Male; D020932:Nerve Growth Factor / Q000494:pharmacology; D016716:PC12 Cells; D010146:Pain / Q000188:drug therapy*; D010455:Peptides / Q000737:chemistry / Q000627:therapeutic use*; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D051381:Rats; D017208:Rats, Wistar; D020917:Receptor, trkA / Q000737:chemistry / Q000627:therapeutic use*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014132:Trachea / Q000187:drug effects
D010455:Peptides; C551301:TrkAd5 peptide; D020932:Nerve Growth Factor; D020917:Receptor, trkA