Background:
Drug resistance is an escalating problem especially in immuno compromised patients susceptible to pathogens. ESS1 is a peptidyl prolyl cis/trans isomerase (PPIase) that is required for the virulence of the pathogenic fungi Candida albicans and Cryptococcus neoformans. Since CaEss1 encoded PPIase enzyme is essential for viability, cells cannot become resistant by this mechanism. The human homolog of ESS1, called Pin1, has been implicated in a wide range of diseases, including cancer and Alzheimer's disease. Differences in interdomain interactions and linker flexibility have been observed in crystallographic and NMR states of the substrate binding domain in Pin1 and the alpha-helix structure in ESS1. These marked differences in conformation between the human and fungal enzymes provide a structural basis for therapeutic targeting of ESS1.
Applications:
- Antifungal drug target
- Combination therapeutic for immuno suppression
Advantages:
- C. albicans, ESS1 encoded PPIase enzyme is essential for viability and cannot become resistant to drugs.
- ESS1 is highly conserved in other pathogenic fungi suggesting that anti-ESS1 inhibitors should have a broad spectrum use.
State of Development:
- X-ray crystallographic and NMR studies have been completed on the structural components of ESS1 and Pin1, the human homolog.
- ESS1 genes have been cloned and characterized from Candida albicans and Cryptococcus neoformans. "Knock-out" strains and expression systems are available.
- Animal models demonstrated importance of ESS1 products to virulence.
Patents:
USPTO 7,217,538
USPTO 6,537,753
Licensing Potential:
Available for license
The Inventors:
Steven D. Hanes, Ph.D.
Research Scientist, Wadsworth Center, Molecular Genetics
Associate Professor, School of Public Health, Biomedical Sciences
Ph.D., Brown University (1988)
Postdoctoral training, Massachusetts General
Hospital/Harvard Medical School
Publications:
Samaranayake D, Atencio D, Morese R, Wade JT, Chaturvedi V, Hanes SD. (2013) Role of Ess1 in Growth, Morphogenetic Switching, and RNA Polymerase II Transcription in Candida albicans. PLoS One 2013;8(3):e59094. doi: 10.1371/journal.pone.0059094. Epub 2013 Mar 14.
McNaughton, L., Li, Z., Van Roey, P., Hanes, S.D., and LeMaster, D. (2010). Restricted domain mobility in the Candida albicans Ess1 prolyl isomerase. Biochim Biophys Acta. 2010 Jul;1804(7):1537-41. Epub 2010 Mar 18.
Singh, N., Ma, Z., Gemmill, T., Wu, X., Rossettini, A., Rabeler, C., Beane, O., DeFiglio, H., Palumbo, M., Morse, R. and Hanes, S. D.(2009). The Ess1 prolyl isomerase is required for transcription termination of small non-coding regulatory RNAs via the Nrd1 pathway. Mol. Cell 2009 Oct 23;36(2): 255-266. Selected for Faculty of 1000 Biology
Ren P, Rossenttini A, Chaturvedi V, Hanes SD (2005) The Ess1 prolyl isomerase is dispensible for growth but required for virulence in Cryptococcus neoformans. Microbiology, 2005 May; 151 (Pt 5): 1593-605.
Vishnu Chaturvedi, Ph.D.
Research Scientist, Wadsworth Center, Mycotic & Parasitic Diseases
Associate Professor, School of Public Health, Biomedical Sciences
Ph.D., University of Delhi, India (1988)
Postdoctoral training, Universidad Complutense, Madrid, University of Cincinnati & Yale University
Publications:
M.A. Pfaller MA, Chaturvedi V, Diekema DJ, Ghannoum MA, Holliday NM, Killian SB, C.C. Knapp CC, Messer SA, Miskov A,and Ramani R. 2008. Clinical evaluation of the Sensititre Yeast One colorimetric antifungal plate for antifungal susceptibility testing of the echinocandins Anidulafungin, Caspofungin, and Micafungin. Journal of Clinical Microbiology.2008 July;46(7):2155-9 Epub 2008 May 7 doi:10.1128/JCM.00493-08.
Chaturvedi V, Ramani R, Ghannoum MA, Killian SB, Holliday N, Knapp C, Ostrosky-Zeichner, Messer SA, Pfaller MA, Iqbal NJ, Arthington-Skaggs BA, Vazquez JA, Sein T, Rex JH,. Walsh TJ. 2008 Multilaboratory testing of antifungal combinations against a quality control isolate of Candida krusei. Antimicrobial Agents Chemotherapy. 2008 Apr;52(4):1500-1502. Epub 2008 Jan 28.
Tavakoli NP, Chaturvedi V. 2008 Laboratory diagnosis of coccidioidomycosis. ASCP Clinical Laboratory. CL-1:1-8. Soares CMA, Mendes-Giannini MJS, Felipe MSS, Chaturvedi V. 2008. A centennial: Discovery of Paraccodidoides brasiliensis. Mycopathologia. 165:179-181.
Summary:
Marketing Summary - CaEss1 Antifungal Target
Contact:
Diane L. Borghoff, B.S., M.S.
Marketing & Licensing Associate – Intellectual Property
Health Research, Inc.
150 Broadway – Suite 560, Menands, New York 12204-2719 U.S.A.
Phone 518-431-1213 Fax 518-431-1234
E-mail: DLB22@healthresearch.org Website: www.healthresearch.org
