AI藥物在近幾年發(fā)展迅速，其中，蛋白質(zhì)從頭設計無疑是AI設計藥物中的重頭戲與熱點。它不僅可以針對不可成藥靶點的藥物和自然中不存在的蛋白進行設計，而且大大縮短了藥物研發(fā)的周期。

華盛頓大學醫(yī)學院的David Baker教授是該領域的強者。當然，AI再牛，也需要用實驗手段去表征設計的蛋白。比如，使用Octet® 非標記分子互作系統(tǒng)檢測設計的蛋白與靶點的親和力。目前，David Baker課題組已使用Octet® 檢測蛋白親和力發(fā)表了近40篇文章，其中CNS文章就有近20篇！(文章列表見文末)

這里，陳老師就介紹一下他今年發(fā)表的幾篇CNS文章。

圖1.(a-c) 從頭設計靶標蛋白的結合蛋白，針對五個靶標，從頭設計結合蛋白，BLI 響應信號值≥陽性對照1/2為候選;（b）RF diffusion成功率高出兩個數(shù)量級; (d) 親和力最高的結合物，結合KD為28nM; (e-h) 結構學驗證

圖3. Octet® 親和力測定發(fā)現(xiàn)設計的單體蛋白聚合顆?？梢耘c識別不同表位抗體結合，表明單體蛋白在聚合顆粒上的構象依舊完整。

-參考文獻

[1] De novo design of protein structure and function with RFdiffusion

JL Watson, D Juergens, NR Bennett, BL Trippe, J Yim… - Nature, 2023 - nature.com

[2] De novo design of modular peptide-binding proteins by superhelical matching.nature,2023

[3] Top-down design of protein architectures with reinforcement learning.

SCIENCEVOL. 380, NO. 6642

[4] Massively parallel de novo protein design for targeted therapeutics

…, X Huang, R Jin, IA Wilson, DH Fuller, D Baker - Nature, 2017 - nature.com

[5] Optimization of affinity, specificity and function of designed influenza inhibitors using deep sequencing

…, H Kamisetty, P Blair, IA Wilson, D Baker - Nature …, 2012 - nature.com

[6] De novo design of picomolar SARS-CoV-2 miniprotein inhibitors

…, L Stewart, MS Diamond, D Veesler, D Baker - Science, 2020 - science.org

[7] De novo design of bioactive protein switches

…, JE Dueber, WRP Novak, H El-Samad, D Baker - Nature, 2019 - nature.com

[8] High-throughput characterization of protein–protein interactions by reprogramming yeast mating

D Younger, S Berger, D Baker… - Proceedings of the …, 2017 - National Acad Sciences

[9] A potent anti-malarial human monoclonal antibody targets circumsporozoite protein minor repeats and neutralizes sporozoites in the liver

…, R Vistein, C Barillas-Mury, R Amino, D Baker… - Immunity, 2020 - Elsevier

[10] Quadrivalent influenza nanoparticle vaccines induce broad protection

…, MC Crank, L Stewart, KK Lee, M Guttman, D Baker… - Nature, 2021 - nature.com

[11] Transferrin receptor targeting by de novo sheet extension

…, DE Ingber, J Abraham, D Baker - Proceedings of the …, 2021 - National Acad Sciences

[12] Receptor subtype discrimination using extensive shape complementary designed interfaces

…, CJ Kuo, KC Garcia, D Baker - Nature structural & …, 2019 - nature.com

[13] Ultrapotent miniproteins targeting the SARS-CoV-2 receptor-binding domain protect against infection and disease

…, R Ravichandran, L Carter, L Stewart, D Baker… - Cell Host & Microbe, 2021 - Elsevier

[14] Targeting HIV Env immunogens to B cell follicles in nonhuman primates through immune complex or protein nanoparticle formulations

…, G Alter, WR Schief, S Crotty, NP King, D Baker… - npj Vaccines, 2020 - nature.com

[15] De novo design of potent and selective mimics of IL-2 and IL-15

…, GJL Bernardes, M Dougan, KC Garcia, D Baker - Nature, 2019 - nature.com

[16] Computational design of proteins targeting the conserved stem region of influenza hemagglutinin

…, C Dreyfus, JE Corn, EM Strauch, IA Wilson, D Baker - Science, 2011 - science.org

[17] Reconfigurable asymmetric protein assemblies through implicit negative design

…, J Decarreau, HM Morris, A Kang, AK Bera, D Baker - Science, 2022 - science.org

[18] Structural and functional evaluation of de novo-designed, two-component nanoparticle carriers for HIV Env trimer immunogens

…, JP Moore, RW Sanders, NP King, D Baker… - PLoS …, 2020 - journals.plos.org

[19] Polyclonal antibody responses to HIV Env immunogens resolved using cryoEM

…, RF Rocha, ZT Berndsen, D Baker… - Nature …, 2021 - nature.com

[20] Induction of potent neutralizing antibody responses by a designed protein nanoparticle vaccine for respiratory syncytial virus

…, KK Lee, D Veesler, CE Correnti, LJ Stewart, D Baker… - Cell, 2019 - Elsevier

[21] Designed protein logic to target cells with precise combinations of surface antigens

…, A Nguyen, S Pun, CE Correnti, SR Riddell, D Baker - Science, 2020 - science.org

[22] De novo design of tyrosine and serine kinase-driven protein switches

…, VH Wysocki, H El-Samad, D Baker - Nature structural & …, 2021 - nature.com

[23] Computational design of trimeric influenza-neutralizing proteins targeting the hemagglutinin receptor binding site

…, AB Ward, P Yager, DH Fuller, IA Wilson, D Baker - Nature …, 2017 - nature.com

[24] Scaffolding protein functional sites using deep learning

…, F DiMaio, B Correia, S Ovchinnikov, D Baker - Science, 2022 - science.org

[25] M*lent designed proteins neutralize SARS-CoV-2 variants of concern and confer protection against infection in mice

…, BS Freedman, JD Bloom, H Ruohola-Baker… - Science translational …, 2022 - science.org

[26] A computationally designed hemagglutinin stem-binding protein provides in vivo protection from influenza independent of a host immune response

…, IA Wilson, A Dagley, DF Smee, D Baker… - PLoS …, 2016 - journals.plos.org

[27] Computational design of a synthetic PD-1 agonist

…, F DiMaio, KV Tarbell, D Baker - Proceedings of the …, 2021 - National Acad Sciences

[28] First critical repressive H3K27me3 marks in embryonic stem cells identified using designed protein inhibitor

…, SH Orkin, D Baker, H Ruohola-Baker - Proceedings of the …, 2017 - National Acad Sciences

[29] Designed proteins assemble antibodies into modular nanocages

…, H Ruohola-Baker, J Mathieu, D Veesler, D Baker - Science, 2021 - science.org

[30] Designed protein logic to target cells with precise combinations of surface antigens

…, A Nguyen, S Pun, CE Correnti, SR Riddell, D Baker - Science, 2020 - science.org

[31] De novo design of tyrosine and serine kinase-driven protein switches

…, VH Wysocki, H El-Samad, D Baker - Nature structural & …, 2021 - nature.com

[32] Computational design of trimeric influenza-neutralizing proteins targeting the hemagglutinin receptor binding site

…, AB Ward, P Yager, DH Fuller, IA Wilson, D Baker - Nature …, 2017 - nature.com

[33] Scaffolding protein functional sites using deep learning

…, F DiMaio, B Correia, S Ovchinnikov, D Baker - Science, 2022 - science.org

[34] M*lent designed proteins neutralize SARS-CoV-2 variants of concern and confer protection against infection in mice

…, BS Freedman, JD Bloom, H Ruohola-Baker… - Science translational …, 2022 - science.org

[35] A computationally designed hemagglutinin stem-binding protein provides in vivo protection from influenza independent of a host immune response

…, IA Wilson, A Dagley, DF Smee, D Baker… - PLoS …, 2016 - journals.plos.org

[36] Computational design of a synthetic PD-1 agonist

…, F DiMaio, KV Tarbell, D Baker - Proceedings of the …, 2021 - National Acad Sciences

[37] First critical repressive H3K27me3 marks in embryonic stem cells identified using designed protein inhibitor

…, SH Orkin, D Baker, H Ruohola-Baker - Proceedings of the …, 2017 - National Acad Sciences

[38] Designed proteins assemble antibodies into modular nanocages

…, H Ruohola-Baker, J Mathieu, D Veesler, D Baker - Science, 2021 - science.org

[39] Computational design of a pH-sensitive IgG binding protein

…, SJ Fleishman, D Baker - Proceedings of the …, 2014 - National Acad Sciences

[40] Design of protein-binding proteins from the target structure alone

…, S Bernard, L Stewart, IA Wilson, H Ruohola-Baker… - Nature, 2022 - nature.com

[41] De novo design of modular and tunable protein biosensors

…, J Wi, HJ Hong, L Stewart, BH Oh, D Baker - Nature, 2021 - nature.com