King Lab | Research
Lab News
Improving the immunogenicity of E. coli FimH via multivalent display on I53-50 nanoparticles
🚨 new paper alert 🚨
Here we apply our protein nanoparticle vaccine platform toward a bacterial indication: uropathogenic E. coli, the primary causative agent of UTIs:
https://bit.ly/4waDqaM
Stabilization of the H5 clade 2.3.4.4b hemagglutinin improves vaccine-elicited neutralizing antibody responses in mice
🚨 new paper alert 🚨
Here we demonstrate increased anti-RBS neutralizing responses elicited by stabilized influenza H5 immunogens:
De novo design of protein nanoparticles with integrated functional motifs
Congratulations to Dr. Dane Zambrano!
Yesterday Dane Zambrano successfully defended her thesis on hybrid lipid-protein nanoparticles! Excellent work Dr. Dane!!
Overview: Designing protein-based nanomaterials for medical applications
Proteins are Nature’s building block of choice for the construction of ‘molecular machines’: stable yet dynamic assemblies with unparalleled abilities in molecular recognition and logic. The King Lab incorporates these features into the design of functional protein-based nanomaterials with the goal of creating new opportunities for the treatment and prevention of disease. We use computational protein design and a variety of biochemical, biophysical, and structural techniques to produce and characterize our novel materials. We are primarily a technology development lab, but our work spans basic science, protein design, protein biochemistry, structural biology, preclinical evaluation, technology transfer, and commercialization.
Computational design of self-assembling protein nanomaterials
Natural proteins often self-assemble into highly ordered nanoscale objects. The sophisticated functions of these molecular machines suggests that the ability to design novel self-assembling protein nanomaterials with customized structures and functions would have immense practical value. The King Lab computationally designs new protein nanomaterials, as well as hybrid biomaterials comprising a variety of macromolecules, with a focus on structures suited for applications in medicine. We are currently working on methods to (i) increase the complexity of the architectures accessible to design, (ii) genetically encode the ability to sense and respond to environmental changes, (iii) incorporate functional elements into our designed materials, and (iv) design materials tailored to display or interact with native proteins of interest. See here for our related publications.
Design of next-generation nanoparticle vaccines
Vaccines are the most effective medical intervention yet discovered, but progress in developing safe and effective vaccines for several important diseases has been slow. Scaffolding engineered forms of pathogen proteins on protein nanoparticles is a promising approach to increase the immunogenicity of subunit vaccines and elicit protective antibody responses. The King Lab has devoted substantial effort to developing next-generation nanoparticle vaccines across many target indications using our designed protein nanomaterials. Our nanoparticle vaccine platform has been rapidly adopted in the field, and in 2022 generated the world’s first computationally designed protein medicine, a nanoparticle vaccine for SARS-CoV-2 (SKYCovione™). Synergistically, we are using cutting-edge deep learning-based design methodologies to stabilize and optimally present a diverse array of antigens on these nanoparticles. We are currently working on extending our antigen and nanoparticle vaccine design strategies to (i) simultaneously incorporate structure-, sequence-, and evolution-based models, (ii) harness rich experimental datasets such as deep mutational scanning data, (iii) enable the display of several classes of important antigens for which no nanoparticle scaffolds currently exist, (iv) enable precise and controllable co-display of multiple antigens or immune modulatory proteins, and (v) enable manufacturing and delivery as either recombinant protein nanoparticles or genetic vaccines. See here for our related publications.
Protein design for programmable immunity
Long-lasting vaccine protection depends on the ability of the immune system to preserve effective antibody responses well beyond the initial exposure. Natural infections and live-attenuated vaccines demonstrate that a single encounter can support protection for decades. Achieving comparable durability with recombinant subunit vaccines, however, remains challenging despite substantial progress in immunogen design, adjuvant development, and delivery. We posit that presenting the correct antigenic structure is necessary but insufficient: durable immunity also requires coordinated control over the cellular pathways, anatomical distribution, and temporal dynamics of the immune response. We are using AI-enabled protein design to encode these functions directly into molecular vaccine components. Our current efforts focus on engineering proteins that (i) engage defined innate immune programs, (ii) regulate antigen trafficking and retention within lymph nodes, (iii) amplify and sustain germinal center responses, and (iv) increase plasma cell production while promoting their long-term survival.
Expanding protein design to programmable glycosylation
Glycosylation is a widespread covalent modification present in the majority of all mammalian proteins. Glycans mediate an incredible diversity of functions including, for example, protein folding and stability, cell signaling and adhesion, and host-pathogen interactions. All-atom modeling and design methods have recently unlocked the ability to precisely program both glycan location and composition using protein structure alone. However, this is at present a completely unexplored area. We are working to develop new methods for (i) programmable control of N-linked glycosylation, (ii) programmable control of O-linked glycosylation, (iii) designing synthetic lectins for a variety of glycans and glycoproteins, and (iv) applying these technologies to applications in vaccines and biologics delivery.