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 ProgressGraham Bessellieu, video editorRachel Shu, on-site editorAnna Magpie, fact-checkingAbhishaike Mahajan, cover artAtalanta Arden-Miller, art directionDavid Hackett, composerWorks in Progress & Open Philanthropy[Correction: The structure of RSV's prefusion F protein was initially determined by X-ray crystallography by Jason McLellan and colleagues, rather than cryo-electron microscopy, although the latter was used to visualize antibody binding and confirm its structure.]

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