DEVELOPMENT OF ELASTASE INHIBITORS TO TREAT EMPHYSEMA

Award Information
Agency:
Department of Health and Human Services
Branch
n/a
Amount:
$50,000.00
Award Year:
1991
Program:
SBIR
Phase:
Phase I
Contract:
n/a
Agency Tracking Number:
16720
Solicitation Year:
n/a
Solicitation Topic Code:
n/a
Solicitation Number:
n/a
Small Business Information
Molecular Design International
P O Box 41777, Memphis, TN, 38174
Hubzone Owned:
N
Socially and Economically Disadvantaged:
N
Woman Owned:
N
Duns:
n/a
Principal Investigator:
Parish, Harlie A
Principal Investigator
(901) 454-1919
Business Contact:
1 R43 HL46621-01
() -
Research Institution:
n/a
Abstract
THE GOAL OF THIS PROJECT IS TO DEVELOP A SYNTHETIC INHIBITOR OF ELASTASE THAT WILL BE EFFECTIVE AND SAFE IN THE TREATMENT OF EMPHYSEMA. TWO DIFFERENT LABORATORIES REPORTED THAT CHLOROMETHYL KETONE (CMK) IS EFFECTIVE IN ANIMAL MODELS OF EMPHYSEMA. HOWEVER, THE CMK ARE TOO TOXIC FOR HUMAN USE. WE HAVE MODIFIED THE STRUCTURE OF THE CMK TO RETAIN ITS ACTIVITY AND DESIRABLE PHYSICAL PROPERTIES BUT REDUCE ITS TOXICITY. OUR INITIAL INHIBITOR, A DERIVATIVE OF N-CBZ- PHENYLALANINE, KI = 3.61 +/- 0.07 X 10-5 M, WAS EVALUATED AGAINST THE SERINE ENZYME CHYMOTRYPSIN. CMK REACTS WITH GLUTATHIONE LEADING TO TOXIC EFFECTS. OUR INHIBITOR DOES NOT REACT WITH GLUTATHIONE. WE WILL SYNTHESIZE TWO ADDITIONAL INHIBITORS AND COMPARE THEM WITH OUR PRESENT INHIBITOR. AN OLIGOPEPTIDE INHIBITOR WILL BE SYNTHESIZED BASED ON OUR BEST INHIBITOR. THIS INHIBITOR WILL BE EVALUATED: 1) AGAINST HUMAN NEUTROPHIL ELASTASE USING TRITIATED CALF LIGAMENT ELASTIN AS SUBSTRATE, 2) FOR CLEARANCE FROM HAMSTER LUNGS, AND 3) IN THE HAMSTER MODEL OF EMPHYSEMA USING HUMAN NEUTROPHIL ELASTASE. THESE OLIGOPEPTIDE INHIBITOR ASSAYS WILL BE CONDUCTED BY DRS. P. J. STONE AND E. C. LUCEY.

* information listed above is at the time of submission.

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