Accession Number : ADA299888

Title :   A New Generic Method for the Production of Protein-Based Inhibitors of Proteins Involved in Cancer Metastasis.

Descriptive Note : Annual rept. 1 Aug 94-31 Jul 95,

Corporate Author : NORTH CAROLINA UNIV AT CHAPEL HILL

Personal Author(s) : Edgell, Marshall H.

PDF Url : ADA299888

Report Date : 31 JUL 1995

Pagination or Media Count : 8

Abstract : Metastasis is a complex, multi-step process involving numerous proteins. Our long-range interest is to design protein-based inhibitors that will block various steps in metastasis. As our first target we have chosen stromelysin, a proteinase implicated in metastasis. There is considerable evidence implicating proteinases in cancer. However, clinical studies using small molecule proteinase inhibitors have uncovered serious toxicity associated with proteinase inhibitors. Our rationale for developing protein-based inhibitors is to utilize their specificity, both as potential inhibitors themselves and as probes of potential side-effects of therapy directed at the specified targets. We have developed a new approach for generating protein-based inhibitors that employs protein engineering to retarget the inhibitory activity of a naturally occurring inhibitor, eglin c, to the targets of interest. Molecular genetics will be used to extend.the reach of traditional protein engineering by making large libraries of structural variants and then using genetic screening and selection strategies to find the best performers. Traditional protein biophysics will then be used to explore the various classes of variants and to make models for what is leading to inhibition. This information will then be used in subsequent cycles of design, construction and screening.

Descriptors :   *PROTEINS, *GENETICS, *CANCER, *METASTASIS, STRATEGY, STRUCTURAL PROPERTIES, TOXICITY, CLINICAL MEDICINE, TARGETS, CYCLES, VARIATIONS, ENGINEERING, THERAPY, MOLECULAR BIOLOGY, GENETIC ENGINEERING, INHIBITION, LIBRARIES, PEPTIDE HYDROLASES, BIOPHYSICS.

Subject Categories : Medicine and Medical Research
      Genetic Engineering and Molecular Biology

Distribution Statement : APPROVED FOR PUBLIC RELEASE