He received a B.S. (chemistry) from Kalamazoo College and a Ph.D. (Chemistry) from the University of Chicago in 1977 working with Emil T. Kaiser and F. Kezdy. His graduate work focused on the design of the oxime resin for solid-phase synthesis, which was used for synthesis of protected peptides and is still in use for various types of combinatorial chemistry today. He also used peptide design to demonstrate that melittin adopts an amphiphilic helical structure, which is responsible for its membrane-disrupting activity.
He first held an industrial position at DuPont Central Research & Development (later DuPont Merck Pharmaceutical Company). He transitioned to academia in 1996, joining the University of Pennsylvania as the George W. Raiziss professor of biochemistry and biophysics and then moved to UCSF in 2011.
His published research includes contributions to the fields of protein design, synthesis of peptidomimetics, and characterization of membrane-active peptides and proteins, most notably the M2 protein.
The M2 proton channel from Influenza A virus. DeGrado’s early work with the groups of Robert Lamb and Larry Pinto established the overall structure and mechanism of the M2 proton channel, which is the target of the anti-influenza drugs, amantadine and rimantadine. A decade later their crystallographic, and NMR structures defined the fine details of the binding site for these drugs and explained the mechanism of the growing problem of amantadine-resistance. With Michael Klein, Robert Lamb and Larry Pinto, DeGrado extensively characterized the physiological properties of many drug-resistant mutants of the channel, identified those most likely to lead to resistance, and designed new drugs to address the problem of drug-resistant forms of influenza A virus.
- 1988 Du Vigneaud Award for Young Investigators in Peptide Research
- 1989 Protein Society Young Investigator Award
- 1992 Eli Lilly Award in Biological Chemistry
- 2005 The American Peptide Society Merrifield Award
- 2008 The ACS Ralph F. Hirschmann Award in Peptide Chemistry
- 2015 The Stein and Moore Award
- "William Degrado, PhD". UCSF. Retrieved 18 January 2014.
- "DeGrado, W. F., and Kaiser, E. T. J. Org. Chem. 40, 1295-1230.". 1980.
- "DeGrado, W. F., Kèzdy, F. J., and Kaiser, E. T. Design, synthesis, and characterization of a cytotoxic peptide with melittin-like activity, J. Amer. Chem. Soc. 103, 679-681.". 1981.
- "Pinto, L. H., Dieckmann, G. R., Gandhi, C. S., Papworth, C. G., Braman, J., Shaughnessy, M. A., Lear, J. D., Lamb, R. A., and DeGrado, W. F. A functionally defined model for the M2 proton channel of influenza A virus suggests a mechanism for its ion selectivity, Proc. Natl. Acad. Sci. U.S.A. 94, 11301-11306.". 1997.
- "Stouffer, A. L., Acharya, R., Salom, D., Levine, A. S., Di Costanzo, L., Soto, C. S., Tereshko, V., Nanda, V., Stayrook, S., and DeGrado, W. F. Structural basis for the function and inhibition of an influenza virus proton channel, Nature 451, 596-599.". 2008.
- "Acharya, R., Carnevale, V., Fiorin, G., Levine, B. G., Polishchuk, A. L., Balannik, V., Samish, I., Lamb, R. A., Pinto, L. H., DeGrado, W. F., and Klein, M. L. Structure and mechanism of proton transport through the transmembrane tetrameric M2 protein bundle of the influenza A virus, Proc Natl Acad Sci U S A 107, 15075-15080.". 2010.
- "Wang, J., Wu, Y., Ma, C., Fiorin, G., Wang, J., Pinto, L. H., Lamb, R. A., Klein, M. L., and DeGrado, W. F. Structure and inhibition of the drug-resistant S31N mutant of the M2 ion channel of influenza A virus, Proc. Natl. Acad. Sci. U.S.A. 110, 1315-1320.". 2013.
- "Cady, S. D., Schmidt-Rohr, K., Wang, J., Soto, C. S., DeGrado, W. F., and Hong, M. Structure of the amantadine binding site of influenza M2 proton channels in lipid bilayers, Nature 463, 689-692.". 2010.
- "Wang, J., Ma, C., Fiorin, G., Carnevale, V., Wang, T., Hu, F., Lamb, R. A., Pinto, L. H., Hong, M., Klein, M. L., and DeGrado, W. F. Molecular dynamics simulation directed rational design of inhibitors targeting drug-resistant mutants of influenza A virus M2, J Am Chem Soc 133, 12834-12841.". 2011.