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

華盛頓大學(xué)醫(yī)學(xué)院的David Baker教授是該領(lǐng)域的強(qiáng)者。當(dāng)然，AI再牛，也需要用實(shí)驗(yàn)手段去表征設(shè)計(jì)的蛋白。比如，使用Octet® 非標(biāo)記分子互作系統(tǒng)檢測設(shè)計(jì)的蛋白與靶點(diǎn)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(shè)計(jì)靶標(biāo)蛋白的結(jié)合蛋白，針對五個(gè)靶標(biāo)，從頭設(shè)計(jì)結(jié)合蛋白，BLI 響應(yīng)信號值≥陽性對照1/2為候選;（b）RF diffusion成功率高出兩個(gè)數(shù)量級; (d) 親和力最高的結(jié)合物，結(jié)合KD為28nM; (e-h) 結(jié)構(gòu)學(xué)驗(yàn)證

圖3. Octet® 親和力測定發(fā)現(xiàn)設(shè)計(jì)的單體蛋白聚合顆粒可以與識別不同表位抗體結(jié)合，表明單體蛋白在聚合顆粒上的構(gòu)象依舊完整。

-參考文獻(xiàn)

[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