From detecting fentanyl to blocking the virus that causes COVID-19, we are pushing the limits of what proteins can do to help meet the challenges of the modern world.
In 2010 our researchers demonstrated that Rosetta-designed proteins can take on shapes that elicit neutralizing antibodies against HIV when injected into animals as vaccine formulations [7, 9]. Four years later, we applied these same methods to create novel immunogens against the respiratory virus RSV, a particularly lethal virus for infants and the elderly . In 2019 we reported our first fully synthetic nanoparticle vaccine targeting RSV . This and other vaccine candidates are now being developed by Icosavax, an IPD spinout. In 2020 we used this same platform technology to create ultrapotent COVID-19 vaccines that in animal testing elicit neutralizing antibodies at levels more than ten times greater than the antigen from authorized mRNA vaccines . Human clinical trials are now underway.
In 2019 we created compact proteins that stimulate the same receptors as IL-2, a powerful immunotherapeutic drug, while avoiding unwanted off-target receptor interactions. These synthetic proteins shrink tumors in mice . This technology is now being developed by our spinout company Neoleukin Therapeutics as a safer platform for cancer immunotherapy.
In 2011 we designed proteins that bind to conserved surfaces on influenza hemagglutinin from the 1918 H1N1 pandemic flu virus . These durable antivirals protect rodents from exposure to lethal amounts of the virus . Our researchers have also shown that these same flu binders can be used as diagnostic reagents in low-cost diagnostic test strips, providing improved performance as an influenza assay compared to a traditional antibody-based capture system . These sensitive reagents can reliably detect less than 100 influenza virus particles on a single nasal swab. In 2020 we used this same platform technology to create potent antivirals for the pandemic coronavirus and adapted them into modular and sensitive biosensors [18, 19].
In 2013 we generated protein binders to the steroid drug digoxigenin, a drug often given to cardiac patients with atrial fibrillation or heart failure . We went on to show that this protein could be used as a sensitive digoxigenin sensor  for point-of-care diagnostic applications, and also as a sensor in cells [12, 13]. In 2017 we used similar methods to design a high-affinity sensor for the potent opioid fentanyl . Two years later we also developed a new protein-based sensor technology called LOCKR and showed that it can be used to direct cancer-killing T cell activity to precise cell populations, thereby avoiding unwanted drug activity. We also demonstrated that LOCKR technology can be reconfigured into a biosensor for detecting vaccine signatures in blood .
In 2011 a team of UW undergraduates working out of the IPD won the grand prize at the annual iGEM competition. They sought to develop a cure for celiac disease and used computational design to re-engineer a natural enzyme to break down gluten in the harsh acidic conditions of the stomach . In 2015 our team published the most advanced version of the enzyme, dubbed Kuma030, which cleaves gluten molecules at sites that are known to cause an immune reaction in those with celiac disease. The enzyme was further developed by our spinout company PvP Biologics, which has been acquired by Takeda.
In 2014 our scientists were the first to demonstrate that computational design can be used to eliminate T-cell epitopes from proteins by altering the amino acid sequence without affecting structure or function . This immune silencing approach enabled collaborators at the National Cancer Institute to improve an immunotoxin used to treat cancer. The new designed immunotoxins maintained good activity, stability, and antitumor activity. Their reduced immunogenicity will enable more effective cancer therapy as more treatment cycles can be given before an immune response is mounted to neutralize the therapy .
- Koday MT, Nelson J, Chevalier A, Koday M, Kalinoski H, Stewart L, Carter L, Nieusma T, Lee PS, Ward AB, Wilson IA, Dagley A, Smee DF, Baker D, Fuller DH: A Computationally Designed Hemagglutinin Stem-Binding Protein Provides In Vivo Protection from Influenza Independent of a Host Immune Response. PLoS pathogens 2016, 12(2):e1005409. PMC#
- Holstein CA, Chevalier A, Bennett S, Anderson CE, Keniston K, Olsen C, Li B, Bales B, Moore DR, Fu E, Baker D, Yager P: Immobilizing affinity proteins to nitrocellulose: a toolbox for paper-based assay developers. Anal Bioanal Chem 2016, 408(5):1335-1346. PMC#
- Silva DA, Yu S, Ulge UY, Spangler JB, Jude KM, Labão-Almeida C, Ali LR, Quijano-Rubio A, Ruterbusch M, Leung I, Biary T, Crowley SJ, Marcos E, Walkey CD, Weitzner BD, Pardo-Avila F, Castellanos J, Carter L, Stewart L, Riddell SR, Pepper M, Bernardes GJL, Dougan M, Garcia CK, Baker D: De novo design of potent and selective mimics of IL-2 and IL-15. Nature 2019, 565(7738):186-191. PMC#30626941
- Mazor R, Eberle JA, Hu X, Vassall AN, Onda M, Beers R, Lee EC, Kreitman RJ, Lee B, Baker D, King C, Hassan R, Benhar I, Pastan I: Recombinant immunotoxin for cancer treatment with low immunogenicity by identification and silencing of human T-cell epitopes. Proceedings of the National Academy of Sciences of the United States of America 2014, 111(23):8571-8576. PMC#4060717
- Wolf C, Siegel JB, Tinberg C, Camarca A, Gianfrani C, Paski S, Guan R, Montelione G, Baker D, Pultz IS: Engineering of Kuma030: A Gliadin Peptidase That Rapidly Degrades Immunogenic Gliadin Peptides in Gastric Conditions. Journal of the American Chemical Society 2015, 137(40):13106-13113. PMC#
- Gordon SR, Stanley EJ, Wolf S, Toland A, Wu SJ, Hadidi D, Mills JH, Baker D, Pultz IS, Siegel JB: Computational design of an alpha-gliadin peptidase. Journal of the American Chemical Society 2012, 134(50):20513-20520. PMC#3526107
- Ofek G, Guenaga FJ, Schief WR, Skinner J, Baker D, Wyatt R, Kwong PD: Elicitation of structure-specific antibodies by epitope scaffolds. Proceedings of the National Academy of Sciences of the United States of America 2010, 107(42):17880-17887. PMC#PMC2964213
- Correia BE, Bates JT, Loomis RJ, Baneyx G, Carrico C, Jardine JG, Rupert P, Correnti C, Kalyuzhniy O, Vittal V, Connell MJ, Stevens E, Schroeter A, Chen M, Macpherson S, Serra AM, Adachi Y, Holmes MA, Li Y, Klevit RE et al: Proof of principle for epitope-focused vaccine design. Nature 2014, 507(7491):201-206. PMC#PMC4260937
- Correia BE, Ban YE, Holmes MA, Xu H, Ellingson K, Kraft Z, Carrico C, Boni E, Sather DN, Zenobia C, Burke KY, Bradley-Hewitt T, Bruhn-Johannsen JF, Kalyuzhniy O, Baker D, Strong RK, Stamatatos L, Schief WR: Computational design of epitope-scaffolds allows induction of antibodies specific for a poorly immunogenic HIV vaccine epitope. Structure 2010, 18(9):1116-1126. PMC#
- Griss R, Schena A, Reymond L, Patiny L, Werner D, Tinberg CE, Baker D, Johnsson K: Bioluminescent sensor proteins for point-of-care therapeutic drug monitoring. Nature chemical biology 2014, 10(7):598-603. PMC#
- Tinberg CE, Khare SD, Dou J, Doyle L, Nelson JW, Schena A, Jankowski W, Kalodimos CG, Johnsson K, Stoddard BL, Baker D: Computational design of ligand-binding proteins with high affinity and selectivity. Nature 2013, 501(7466):212-216. PMC#3898436
- Taylor ND, Garruss AS, Moretti R, Chan S, Arbing MA, Cascio D, Rogers JK, Isaacs FJ, Kosuri S, Baker D, Fields S, Church GM, Raman S: Engineering an allosteric transcription factor to respond to new ligands. Nature methods 2016, 13(2):177-183. PMC#
- Feng J, Jester BW, Tinberg CE, Mandell DJ, Antunes MS, Chari R, Morey KJ, Rios X, Medford JI, Church GM, Fields S, Baker D: A general strategy to construct small molecule biosensors in eukaryotes. eLife 2015, 4. PMC#PMC4739774
- Fleishman SJ, Whitehead TA, Ekiert DC, Dreyfus C, Corn JE, Strauch EM, Wilson IA, Baker D: Computational design of proteins targeting the conserved stem region of influenza hemagglutinin. Science 2011, 332(6031):816-821. PMC#3164876
- King C, Garza EN, Mazor R, Linehan JL, Pastan I, Pepper M, Baker D: Removing T-cell epitopes with computational protein design. Proceedings of the National Academy of Sciences of the United States of America 2014, 111(23):8577-8582. PMC#4060723
- Bick MJ, Greisen PJ, Morey KJ, Antunes MS, La D, Sankaran B, Reymond L, Johnsson K, Medford JI, Baker D, Cravatt, BF: Computational design of environmental sensors for the potent opioid fentanyl. eLife 2017, 6. PMC#5655540
- Walls AC, Fiala B, Schäfer S, […] , Helen Y. Chu HY, Lee KK, Fuller DH, Baric RS, Kellam P, Carter L, Pepper M, Sheahan TP, Veesler D, King NP: Elicitation of potent neutralizing antibody responses by designed protein nanoparticle vaccines for SARS-CoV-2. Cell 2020, PMC#7604136
- Cao L, Goreshnik I, Coventry B, Case, JB, Miller L […], Diamond, MS; Veesler D, Baker D: De novo design of picomolar SARS-CoV-2 miniprotein inhibitors. Science 2020, PMC#7857403
- Quijano-Rubio A, Yeh H, Park J, Lee H, Langan RA, Boyken SE, Lajoie ML, Cao L, Chow CM, Miranda MC, Wi J, Hong HJ, Stewart L, Oh B-H Baker D: De novo design of modular and tunable allosteric biosensors. Nature, 2021. PMC#7386493