Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 17, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2021569118
Keywords
computational protein design; drug delivery; neurological disease; transferrin receptor; blood?brain barrier
Categories
Funding
- European Molecular Biology Organization long-term fellowship [ALTF 1295-2015]
- Washington Research Foundation Innovation Fellowship [5R01AG063845-02]
- Alzheimer's Disease Research Center [P50 AG005136]
- Donald and Jo Anne Petersen Endowment for Accelerating Advancements in Alzheimer's Disease Research, an NIH Director's Early Independence Award [DP5OD023084]
- Burroughs Wellcome Fund Career Award for Medical Scientists
- NIH [P41GM128577]
- Wyss Institute for Biologically Inspired Engineering
- National Institute of General Medical Sciences from the NIH [P30 GM124165]
- NIH-Office of Research Infrastructure Programs High-End Instrumentation grant [S10 RR029205]
- DOE Office of Science [DE-AC02-06CH11357]
Ask authors/readers for more resources
The challenge of designing polar protein-protein interactions is addressed by a computational approach utilizing complementary geometrically matched beta strands. Specifically designed proteins successfully bind to the human transferrin receptor, enabling drug delivery across the blood-brain barrier. This design strategy offers a general approach for creating binders to protein targets with exposed surface beta edge strands.
The de novo design of polar protein?protein interactions is challenging because of the thermodynamic cost of stripping water away from the polar groups. Here, we describe a general approach for designing proteins which complement exposed polar backbone groups at the edge of beta sheets with geometrically matched beta strands. We used this approach to computationally design small proteins that bind to an exposed beta sheet on the human transferrin receptor (hTfR), which shuttles interacting proteins across the blood? brain barrier (BBB), opening up avenues for drug delivery into the brain. We describe a design which binds hTfR with a 20 nM Kd, is hyperstable, and crosses an in vitro microfluidic organ-on-a-chip model of the human BBB. Our design approach provides a general strategy for creating binders to protein targets with exposed surface beta edge strands.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available