Hacking proteins with AI

11 snips

Oct 1, 2025

Artificial intelligence is revolutionizing protein design, aiming to create safer and more effective vaccines. Tools like AlphaFold and ProteinMPNN are leading the charge in re-engineering proteins, particularly targeting the Strep A antigen for potential vaccines. The discussion highlights how modifying proteins can enhance manufacturability and stability. Listeners learn about the intricate processes of testing candidates in labs and how breakthroughs from AI have already impacted COVID and RSV vaccine development. Can we design entirely novel proteins using AI? Tune in to find out!

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INSIGHT

AI Transforms Protein Design

AI now predicts protein structures and enables design of proteins never seen in nature.
This unlocks new medicines, improved vaccines, and engineered proteins for many industries.

INSIGHT

Target Surface Antigens For Strep A

Targeting surface proteins like C5a peptidase can enable vaccines against strep A.
A properly chosen antigen can prevent immune confusion that leads to rheumatic heart disease.

ANECDOTE

Hands-On At Institute For Protein Design

Jacob visited the Institute for Protein Design to experiment with ProteinMPNN on a strep A antigen.
He used the tool to propose redesigned versions of the antigen as vaccine candidates.

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Nature didn’t evolve all the proteins we need, but maybe artificial intelligence can help. Jacob and Saloni explore how tools like AlphaFold and ProteinMPNN are helping researchers re-engineer proteins, to make them safer, more stable, and more effective. They talk about how new technologies could help make a long-sought vaccine against Strep A, which causes scarlet fever and rheumatic heart disease, and how similar tools have already led to breakthroughs against COVID and RSV.

Hard Drugs is a new podcast from Works in Progress and Open Philanthropy about medical innovation presented by Saloni Dattani and Jacob Trefethen.

Saloni’s substack newsletter: https://www.scientificdiscovery.dev/

Jacob’s blog: https://blog.jacobtrefethen.com/

Courses:

EMBL-EBI. AlphaFold: A practical guide https://www.ebi.ac.uk/training/online/courses/alphafold/

Articles:

Monica Jain et al. (2022) Exosite binding modulates the specificity of the immunomodulatory enzyme ScpA, a C5a inactivating bacterial protease. https://pmc.ncbi.nlm.nih.gov/articles/PMC9464890/
Jakki Cooney et al. (2008) Crystal structure of C5a peptidase https://www.rcsb.org/structure/3EIF
Hui Li et al. (2017) Mutagenesis and immunological evaluation of group A streptococcal C5a peptidase as an antigen for vaccine development and as a carrier protein for glycoconjugate vaccine design https://pubs.rsc.org/en/content/articlelanding/2017/ra/c7ra07923k

Lectures:

Rosetta Commons (2024) AlphaFold – ML for protein structure prediction https://www.youtube.com/watch?v=SVrn8_8aKO8
Rosetta Commons (2024) MPNN – ML for protein sequence design https://www.youtube.com/watch?v=6z4XmUAwdNA

Acknowledgements:

Aria Babu, editor at Works in Progress
Graham Bessellieu, video editor
Rachel Su, on-site editor
Anna Magpie, fact-checking
Abhishaike Mahajan, cover art
Atalanta Arden-Miller, art direction
David Hackett, composer

Works in Progress & Open Philanthropy

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