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研究分野生物医学と臨床科学腫瘍学とがん発生分子標的
設計されたエンドサイトーシス誘発タンパク質は標的を分解し,信号を放大する.

設計されたエンドサイトーシス誘発タンパク質は標的を分解し,信号を放大する.

Buwei Huang ^1,2,3, Mohamad Abedi ^1,2, Green Ahn ⁴, Brian Coventry ^1,2,5, Isaac Sappington ^1,2, Cong Tang ⁶, Rong Wang ⁷, Thomas Schlichthaerle ^1,2, Jason Z Zhang ^1,2, Yujia Wang ², Inna Goreshnik ^1,2,5, Ching Wen Chiu ², Adam Chazin-Gray ^1,2, Sidney Chan ², Stacey Gerben ², Analisa Murray ², Shunzhi Wang ^1,2, Jason O'Neill ⁸, Li Yi ⁸, Ronald Yeh ⁸, Ayesha Misquith ⁸, Anitra Wolf ⁸, Luke M Tomasovic ^9,10, Dan I Piraner ¹¹, Maria J Duran Gonzalez ¹¹, Nathaniel R Bennett ^1,2, Preetham Venkatesh ^1,2, Maggie Ahlrichs ², Craig Dobbins ², Wei Yang ^1,2, Xinru Wang ^1,2, Danny D Sahtoe ¹², Dionne Vafeados ², Rubul Mout ¹³, Shirin Shivaei ¹⁴, Longxing Cao ¹⁵, Lauren Carter ², Lance Stewart ², Jamie B Spangler ⁸, Kole T Roybal ¹¹, Per Jr Greisen ⁸, Xiaochun Li ⁷, Gonçalo J L Bernardes ^6,16, Carolyn R Bertozzi ^4,17,18, David Baker ^19,20,21

Buwei Huang ^1,2,3, Mohamad Abedi ^1,2, Green Ahn ⁴

¹Department of Biochemistry, University of Washington, Seattle, WA, USA.
²Institute for Protein Design, University of Washington, Seattle, WA, USA.
³Department of Bioengineering, University of Washington, Seattle, WA, USA.
⁴Department of Chemistry, Stanford University, Stanford, CA, USA.
⁵Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA.
⁶Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
⁷Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁸Novo Nordisk, Måløv, Denmark.
⁹Departments of Biomedical Engineering and Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
¹⁰Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹¹Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA, USA.
¹²Hubrecht Institute, Utrecht, The Netherlands.
¹³Harvard Medical School, Harvard University, Boston, MA, USA.
¹⁴Division of Biology and Bioengineering, California Institute of Technology, Pasadena, CA, USA.
¹⁵School of Life Sciences, Westlake University, Hangzhou, China.
¹⁶Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK.
¹⁷Howard Hughes Medical Institute, Stanford, CA, USA.
¹⁸Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
¹⁹Department of Biochemistry, University of Washington, Seattle, WA, USA. dabaker@uw.edu.
²⁰Institute for Protein Design, University of Washington, Seattle, WA, USA. dabaker@uw.edu.
²¹Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA. dabaker@uw.edu.

⁰Department of Biochemistry, University of Washington, Seattle, WA, USA.

Nature +

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2024年9月25日

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PubMedで要約を見る

まとめ

この要約は機械生成です。

研究者は,エンドサイトーシス誘発結合タンパク質 (EndoTags) のための新しい計算設計アプローチを開発しました. これらのEndoTagsは,標的型タンパク質の分解とシグナル活性化を促進し,様々な疾患の治療に重要な可能性を秘めています.

科学分野

バイオテクノロジーと分子工学
薬の発見と開発
細胞生物学と受容体取引

背景

細胞表面受容体のエンドサイトーシスとリソソームの密輸は,重要な生物学的プロセスです.
LYTACsやKineTACsのような既存の治療戦略は,分解のためにタンパク質を標的とするが,リガンドの競争や化学的改変の要件などの制限に直面する.
治療目的で受容体媒介性内細胞化を誘導するための多用途で遺伝的にコード可能な方法が必要である.

研究の目的

既存のタンパク質分解技術の限界を克服する新しい内細胞分裂誘発結合タンパク質 (EndoTags) を計算的に設計する.
EndoTagsの効能を証明するために,リゾソームの密輸と標的タンパク質の分解を媒介する.
EndoTagsの標的分解誘導体,シグナリング活性化剤,細胞吸収強化剤としての治療の可能性を探求する.

主な方法

エンドサイトーシス誘発結合タンパク質 (EndoTags) の計算設計.
特定の受容体 (IGF2R,ASGPR,ソルチリン,トランスファーリン受容体) を標的とする溶解性またはトランスメブランタンパク質結合に設計されたEndoTagsの融合.
ネズミの腫瘍モデルにおけるEndoTag媒介によるリソソームの流通,標的の分解,および治療効果のインビトロおよびインビボ検証 (PD- L1抗体融合).

主要な成果

多数の受容体に対するEndoTagsの設計と検証が成功し,ライソソームの密輸と結合剤への標的の分解を証明した.
PD- L1抗体に対するEndoTag融合は,抗体単独と比較してマウス腫瘍モデルでの治療効果を著しく高めました.
EndoTag技術は,モジュール化,遺伝子コード化,および特異性のためのゲート制御,局所的分泌,および強化されたシグナリング (ほぼ100倍増加) を可能にします.

結論

EndoTagsは,前回のアプローチの限界を克服し,標的型タンパク質分解のための強力で汎用的なプラットフォームです.
EndoTagsのモジュラリティと遺伝子コード化性は,精密な制御と製造を含む治療開発に重要な利点を提供します.
EndoTagsは,標的の分解,内細胞化に依存する経路の活性化,および薬物およびRNA結合体の細胞吸収の強化に相当な治療効果を期待しています.

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