We are interested in the chemistry and biology of steroids. My laboratory specializes in natural products chemistry as it relates to the synthesis of steroids and steroid analogues. The compounds prepared in the laboratory are then studied in laboratories of colleagues throughout the university, and elsewhere, who share with us a common interest in the biological actions of steroids.
Currently our efforts are focused in four main areas:
- Neuroactive steroids
- Neuroprotective steroids
- Cholesterol homeostasis
- Steroid effects on the physical properties of cellular membranes
Neuroactive steroids affect the functioning of ion-channels involved in synaptic transmission in the central nervous systems. Some of these neuroactive steroids are potent anesthetics and the chemistry carried out on this project is designed either to provide mechanistic information on how steroids cause anesthesia or to provide new structure–activity data for the development of new anesthetic steroids.
Neuroprotective steroids are steroids that prevent or reduce neurodegeneration. We are interested in steroids that prevent neuronal cell death caused by oxidative damage.
The complex process whereby cells regulate the production and distribution of cholesterol in cells is incompletely understood. Steroids prepared in this project area are selected for their ability to provide a better understanding of this complex regulation.
Finally, we are interested in understanding the role that cholesterol–sphingomyelin rafts play in cell signaling. We are studying how cell signaling pathways mediated by proteins localized in rafts are altered by changes in the physical properties of their membrane environment.
Keywords: steroid, neurosteroid, neuroprotection, cholesterol, sphingomyelin.
Education and Training
Loyola College, Baltimore, MD B.S. 1967 Chemistry
Johns Hopkins Univ., Baltimore, MD M.A. 1969 Chemistry
Johns Hopkins Univ., Baltimore, MD Ph.D. 1973 Chemistry
Johns Hopkins Univ., Baltimore, MD 73-74 Chemistry
Johns Hopkins Univ., Baltimore, MD 74-77 Pharmacology
1990-present Professor, Department of Molecular Biology and Pharmacology, Washington University Medical School, St. Louis, Missouri
1983-1990 Associate Professor, Department of Pharmacology, Washington University Medical School, St. Louis, Missouri
1977-1983 Assistant Professor, Department of Pharmacology, Washington
University Medical School, St. Louis, Missouri
Honors and Awards
National Academy of Inventors Fellow 2022
Chancellor’s Award for Innovation and Entrepreneurship 2020
School of Medicine Alumni Assoc. Faculty Achievement Award 2020
Andrew C. and Barbara B. Taylor Distinguished Prof. of Psychiatry 2019
National Academy of Inventors Senior Member 2019
School of Medicine Distinguish Investigator Award 2017
American Chemical Society St. Louis Award 2004
- Feltes, M., Moores, S., Gale, S.E., Krishnan, K., Mydock-McGrane, L., Covey, D.F., Ory, D.S. and Schaffer, J.E. Synthesis and characterization of diazirine alkyne probes for the study of intracellular cholesterol trafficking. J. Lipid. Res., 60, 707-716 (2019).
- Chen, Z.-W., Bracamontes, J.R., Budelier, M.M., Germann, A.L., Shin, D.J., Kathiresan, K., Qian, M.X., Manion, B., Cheng, W.W.L., Reichert, D.E., Akk, G., Covey, D.F., Evers, A.S. Multiple functional neurosteroid binding sites on GABAA receptors. PLOS Biol., e3000157 (2019).
- Sugasawa, Y., Cheng, W.W.L., Bracamontes, J.R., Chen, Z-W., Wang, L., Germann, A.L., Pierce, S.R., Senneff, T.C., Krishnan, K., Reichert, D.E., Covery, D.F., Akk, G. and Evers, A.S. Site-specific effects of neurosteroids on GABAA receptor activation and desensitization. eLife, 9, e55331 (2020).
- Ishikawa, M., Takaseki, S., Yoshitomi, T., Covey, D.F., Zorumski, C.F. and Izumi, Y. The neurosteroid allopregnanolone protects retinal neurons by effects on autophagy and GABAA receptors in rat glaucoma models. Autophagy, 17, 743-760 (2021).
- Krishnan, K., Qian, M., Feltes, M., Chen, Z-W., Gale, S., Lei, W., Sugasawa, Y., Reichert, D.E., Schaffer, J.E., Ory, D.S., Evers, A.S. and Covey, D.F. Validation of trifluoromethylphenyl diazirine cholesterol analogues as cholesterol mimetics and photolabeling reagents. ACS Chem. Biol., 16, 1493-1507 (2021).
- Dietzen, N.M., Arcario, M.J., Chen, L.J., Petroff, J.T., Moreland, T.K., Krishnan, K., Brannigan, G., Covey, D.F. and Cheng, W.W.L. Polyunsaturated fatty acids inhibit a pentameric ligand-gated ion channel through one of two binding sites. eLife, 22, e74306 (2022).