IDENTIFYING NOVEL ANTIFUNGAL THERAPEUTICS

DESCRIPTION: (Adapted from applicant's abstract) Fungal pathogens are responsible for a variety of opportunistic diseases related to AIDS. This proposal describes a high throughput screen for identifying new antifungal agents specifically targeted against protein translation by screening for growth in two yeast mutants, one overexpressing yeast elongation factor EF-3, the other underexpressing the same factor. $ = TOTAL AWARD AMTS & NOT LIMITED TO PORTION OF PROJECT RELATED TO SUBJECT OF SEARCH SUBPROJECT $ = TOTAL AWARD AMOUNT DIVIDED BY NUMBER OF SUBPROJECTS SOURCE: CRISP FORMAT F FY 97 LAST UPDATE 04-07-98 1QUERY 1536 ID SEARCH 06/01/98 PAGE 100 --PROJECT NUMBER......1 R43 AI43285-01 INVESTIGATOR NAME/ADDRESS FY 97 CARPENTER, THOMAS R IRG/INTRAMURAL UNIT..ZRG5 HTI BIO-PRODUCTS AWARD AMOUNT......... $100,000 P O BOX 1319 RAMONA, CA 92065 PERFORMING ORGANIZATION: HTI BIO-PRODUCTS, INC. TITLE HIGH THROUGHPUT SCREENING FOR ANTIFUNGAL AGENTS ABSTRACT: The focus of this proposal is to produce a high-throughput assay to assess the specificity and inhibitory efficacy of antifungal drug candidates. Mycoses are an increasingly important complication in immunocompromised patients. Long-term treatments can induce drug- related complications and select for drug-resistant strains. The target of perhaps the most important family of antifungals, the azoles, is the inhibition of a P450 enzyme, lanosterol 14-alpha-demethylase (LDM). LDM is required for the production of ergosterol, an essential cell membrane constituent, in yeasts and for the production of cholesterol in man. New antifungals able to eradicate resistant strains of fungi are needed that specifically target the fungal LDM. The PI's assay takes advantage of the requirement for LDM in oxidative growth of Saccharomyces cerevisiae. S. Cerevisiae will be transformed with human or Candida albicans coding sequences for LDM and the endogenous gene for LDM will be deleted by recombinatorial techniques, resulting in the exclusive expression of exogenous LDM. Decreased growth among the two transformants will provide a test for specificity against Candida LDM and as a means for assessing the inhibitory capacity of each LDM-targeted antifungal. The investigator's goal is to provide this service as an inexpensive, efficient alternative to more traditional pre-trial testing of antifungal candidates. $ = TOTAL AWARD AMTS & NOT LIMITED TO PORTION OF PROJECT RELATED TO SUBJECT OF SEARCH SUBPROJECT $ = TOTAL AWARD AMOUNT DIVIDED BY NUMBER OF SUBPROJECTS SOURCE: CRISP FORMAT F FY 97 LAST UPDATE 04-07-98 1QUERY 1536 ID SEARCH 06/01/98 PAGE 101 --PROJECT NUMBER......1 R43 AR43059-01A3 INVESTIGATOR NAME/ADDRESS FY 97 REINHOLDTSEN, PAUL A IRG/INTRAMURAL UNIT..ZRG7 METRIUM AWARD AMOUNT......... $99,952 2600 SECOND AVENUE #1102 SEATTLE, WA 98121 PERFORMING ORGANIZATION: METRIUM TITLE AN ADVANCED MUSCULOSKELETAL ANALYSIS SYSTEM NO ABSTRACT ON FILE $ = TOTAL AWARD AMTS & NOT LIMITED TO PORTION OF PROJECT RELATED TO SUBJECT OF SEARCH SUBPROJECT $ = TOTAL AWARD AMOUNT DIVIDED BY NUMBER OF SUBPROJECTS SOURCE: CRISP FORMAT F FY 97 LAST UPDATE 04-07-98 1QUERY 1536 ID SEARCH 06/01/98 PAGE 102 --PROJECT NUMBER......2 R44 AR43680-02 INVESTIGATOR NAME/ADDRESS FY 97 SHEFER, RUTH E IRG/INTRAMURAL UNIT..ZRG7 NEWTON SCIENTIFIC, INC AWARD AMOUNT......... $407,732 245 BENT ST CAMBRIDGE, MA 02141 PERFORMING ORGANIZATION: NEWTON SCIENTIFIC, INC. TITLE NEUTRON CAPTURE SYNOVECTOMY FOR RHEUMATOID ARTHRITIS ABSTRACT: The goal of this program is to determine the feasibility of synovectomy using the 10B(n,alpha)7 Li nuclear reaction with an external neutron beam for the treatment of rheumatoid arthritis (RA). This therapy has two potential advantages over surgical or radiation synovectomy with beta- emitters for RA: it is non-invasive and it does not require the administration of radioactive materials to the patient. Recent experiments have shown that very high boron concentrations can be achieved in active human synovium in vitro. However, the required neutron beam characteristics for therapy are presently unknown. In Phase I, Monte Carlo simulation techniques will be used to determine the required boron distribution and neutron beam parameters for successful therapy of the human synovial joints most commonly involved in RA. An optimized accelerator-based neutron beam design which minimizes radiation dose to non-target tissues in neutron capture synovectomy will then be developed. This work will lead to the construction of a neutron therapy beamline in Phase II and will provide the quantitative basis for future in vivo studies of synovial tissue ablation using the 10B(n,alpha) reaction.