The goal of this research plan is two-fold. First, to identify which of the 133 amino acid residues comprising the interleukin 2 primary sequence participate in receptor binding and the expression of biologic activity; and second, to utilize this information to design IL-2 related peptides with potential therapeutic utility having agonist and antagonist activity. We will utilize recombinant DNA derived proteins, synthetic peptides and monoclonal antibodies combined with analytical, physical and biologic assay methods to achieve the first part of our goal. Then, knowing which regions of IL-2 are important, we will use computer assisted molecular modeling to help design analogs which retain the proper stereochemical relationships required for agonist activity or receptor binding. We will also design potential IL-2 antagonists using similar techniques and the knowledge of the sequence of an Il-2 binding cell surface protein. We will prepare and purify the compounds and determine their activity in the Il-2 bioassay and competitive radioreceptor assay.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI023398-02
Application #
3135433
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1986-07-01
Project End
1989-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
2
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Dartmouth College
Department
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Lee, B L; Ciardelli, T L (1997) Structural modifications of interleukin-2 at positions 47 and 65. Biochem Biophys Res Commun 233:309-15
Chang, D Z; Wu, Z; Ciardelli, T L (1996) A point mutation in interleukin-2 that alters ligand internalization. J Biol Chem 271:13349-55
Chang, D Z; Tasayco, M L; Ciardelli, T L (1995) Structural analogs of interleukin-2: a point mutation that facilitates biological response. Mol Pharmacol 47:206-11
Nielsen, O H; Ciardelli, T; Wu, Z et al. (1995) Circulating soluble interleukin-2 receptor alpha and beta chain in inflammatory bowel disease. Am J Gastroenterol 90:1301-6
Berndt, W G; Chang, D Z; Smith, K A et al. (1994) Mutagenic analysis of a receptor contact site on interleukin-2: preparation of an IL-2 analog with increased potency. Biochemistry 33:6571-7
Sana, T R; Wu, Z; Smith, K A et al. (1994) Expression and ligand binding characterization of the beta-subunit (p75) ectodomain of the interleukin-2 receptor. Biochemistry 33:5838-45
Wu, Z; Eaton, S F; Laue, T M et al. (1994) Coiled-coil molecular recognition: directed solution assembly of receptor ectodomains. Protein Eng 7:1137-44
Buchli, P; Ciardelli, T (1993) Structural and biologic properties of a human aspartic acid-126 interleukin-2 analog. Arch Biochem Biophys 307:411-5
Landgraf, B E; Goldstein, B; Williams, D P et al. (1992) Recombinant interleukin-2 analogs. Dynamic probes for receptor structure. J Biol Chem 267:18511-9
Landgraf, B E; Williams, D P; Murphy, J R et al. (1991) Conformational perturbation of interleukin-2: a strategy for the design of cytokine analogs. Proteins 9:207-16

Showing the most recent 10 out of 11 publications