Brilacidin as a Successful Example of De Novo Drug Design

Linked to below is a video presentation — "Proteins in Medicine: De Novo Protein Design" — as part of the 2017 Molecular Frontiers Symposium convened in Budapest, Hungary. The talk was given by invited speaker, Dr. William DeGrado, a renowned chemist and faculty member in the Department of Pharmaceutical Chemistry and head of the DeGrado Lab, which focuses on small molecule and protein design, at the University of California San Francisco.

As Symposium materials note: “Started in 2006, Molecular Frontiers operates as a non-profit organization, hosted by the Royal Swedish Academy of Sciences. Its Scientific Advisory Board, a group of eminent scientists including many Nobel Prize laureates, represent expertise from a wide range of molecular science disciplines.”

Dr. DeGrado was one of the original scientists involved, while at the University of Pennsylvania, in the discovery and subsequent development (see recent mechanistic studies) of Brilacidin and the larger Innovation Pharmaceuticals’ Host Defense Protein (HDP)-mimetic platform.

The early part of his talk covers the biocomputational beginnings (pdf) of Brilacidin, a promising immunomodulatory drug candidate currently being evaluated in mid-stage clinical trials. Brilacidin, based on insights gleaned from frog peptides, is a successful example of de novo protein design, described as: "the process of using peptide sequences that are not existent in, but inspired by nature" to build molecules as potential innovative therapeutics with novel attributes and applications. As to drug development, such novel synthetic design strategies of proteins ("the workhorses of all living creatures") allow for improved pharmacokinetic properties and enhanced target specificity. (For more information, see "Therapeutic Peptides: Historical Perspectives, Current Development Trends, and Future Directions" in Bioorganic & Medicinal Chemstry, July 2017; and: "Development Trends for Peptide Therapeutics: Status in 2016," pdf.)

Dr. DeGrado has co-authored over 370 articles (list of publications), holds more than 25 patents, and is a member of the National Academy of Sciences, elected in 1999. In 2003, he was presented (pdf) with the Merrifield Award by the American Peptide Society. He received The Protein Society's Stein and Moore Award in 2015 and, most recently, was presented with the 2017 Biopolymers Murray Goodman Memorial Prize.

In August 2014, the American Chemical Society convened a symposium in honor of him tied to his "pioneering work." And in July 2015, an issue of Peptide Science was dedicated (pdf) to him as an appreciation of his major contributions to the peptide and protein science field:

"Bill's work is truly interdisciplinary having made significant impact in drug discovery, peptide chemistry, protein design, folding, structure and function, as well as membrane biophysics. ... Legend has it that Bill can just look at a primary sequence and tell you how it'll fold. Rosetta-schmosetta -- who needs it when you got Bill!"

Source: “ Big Bad Bill is sweet William now .” Joel Schneider. Editorial.  Peptide Science . Vol 104, Issue 4 (July 2015), pages v-vi.

Source: “Big Bad Bill is sweet William now.” Joel Schneider. Editorial. Peptide Science. Vol 104, Issue 4 (July 2015), pages v-vi.

Almost everything in biomedicine could be impacted by an ability to build better proteins — Harvard synthetic biologist George Church

Source: Robert F. Service. “This Protein Designer Aims to Revolutionize Medicines and Materials.” Science Magazine. July 21, 2016.