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
Neuroactive steroids affect the functioning of ion-channels involved in synaptic transmission in the central nervous systems. Neuroactive steroids modulate the activity of GABA and NMDA receptors, and current chemistry efforts are directed toward identifying binding sites for neurosteroids on these receptors. Chemistry is also being used to prepare compounds for use in studies to determine the mechanism of action for antidepressant and neuroprotective actions of neurosteroids.
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.
Keywords: steroid chemistry, 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
2013-present, Professor, Department of Psychiatry, Washington University Medical School, St. Louis, Missouri
2013-present, Professor, Department of Anesthesiology, Washington University Medical School, St. Louis, Missouri
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
- Tateiwa H, Chintala SM, Chen Z, Wang L, Amtashar F, Bracamontes J, Germann AL, Pierce SR, Covey DF, Akk G, Evers AS. The Mechanism of Enantioselective Neurosteroid Actions on GABAA Receptors. Biomolecules. 2023 Feb 9;13(2):341
- Manzella FM, Cabrera OH, Wilkey D, Fine-Raquet B, Klawitter J, Krishnan K, Covey DF, Jevtovic-Todorovic V, Todorovic SM. Sex-specific hypnotic effects of the neuroactive steroid (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile are mediated by peripheral metabolism into an active hypnotic steroid. Br J Anaesth. 2023 Feb;130(2):154-164.
- Kinnebrew, M., Woolley, R.E., Ansell, T.B., Byrne, E.F.X., Frigui, S., Luchetti, G., Sircar, R., Nachtergaele, S., Mydock-McGrane, L., Krishnan, K., Newstead, S., Sansom, M.S.P., Covey, D.F., Siebold, C. and Rohatgi, R. Patched 1 regulates smoothened by controlling sterol binding to its extracellular cysteine-rich domain. Sci. Adv., 8, eabm5563 (2022).
- Shin, H.R., Citron, Y.R. Wang, L., Tribouillard, L., Goul, C.S., Stipp, R., Sugasawa, Y., Jain, A., Samson, N., Lim, C.Y., Davis, O.B., Castaneda-Carpio, D., Qian, M., Nomura, D.K., Perera, R.M., Park, E., Covey, D.F., Laplante, M., Evers, A.S. and Zoncu, R. Lysosomal GPCR-like protein LYCHOS signals cholesterol sufficiency to mTORC1, Science, 377, 1290-1298 (2022).
- Ishikawa, M., Nakazawa, T., Kunikata, H., Sato, K., Yoshitomi, T., Krishnan, K., Covey, D.F., Zorumski, C.F. and Izumi, Y. The enantiomer of allopregnanolone prevents pressure-mediated retinal degeneration via autophagy. Front. Pharmacol., 13, 855779 (2022).
- 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).