Expanding the design space of protein-small molecule conjugates

扩大蛋白质-小分子缀合物的设计空间

基本信息

  • 批准号:
    10729980
  • 负责人:
  • 金额:
    $ 39.88万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-08-01 至 2026-07-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY/ABSTRACT Targeted therapy and targeted drug delivery have revolutionized clinical care of complex disease whenever these options are available – and, yet, only a minority of patients have access to these precision medicine approaches where their care is based on the molecular basis of their disease. Such molecular targeting leads to better patient outcomes and fewer toxic side effects compared to traditional treatment approaches, for a range of diseases. As part of expanding precision medicine to all patients with complex diseases, there is a critical need to meet the molecular targeting gaps in clinical care where such options currently do not exist. Protein- drug conjugates have immense promise in targeted therapy and drug delivery applications, with a number of recent successes in the form of antibody-drug conjugates (ADCs) for cancer therapy. However, numerous design challenges for protein-drug conjugates remain, including narrow therapeutic windows and difficulty in translating success in oncology to other clinical indications. Even within oncology, solid tumors remain significantly more difficult to treat than hematological cancers. Our hypothesis is that the current set of modular components in the design space is limiting and leads to many of the current challenges. Therefore, there is an unmet need to create and validate protein-drug conjugate components and combinations beyond those currently being used. The overall goal of this proposed research is to expand the design space for protein-drug conjugates, enabling this class of molecules to have further success in a wider range of applications in biotechnology and medicine. We propose to validate scaffold proteins and side-chain reactive polymers as modular components for novel protein-drug conjugate structures. As a model protein scaffold for this work, we will use the Fn3 polypeptide fold, which has been demonstrated to be extremely versatile for engineering molecular recognition using rational and directed evolution approaches. We propose to modify model Fn3 proteins with canonical and non-canonical amino acids to enable site-specific bioconjugation reactions (Aim 1). As a novel linker system for protein-drug conjugates, we propose to use side-chain reactive poly(PFPA), as a model polymer for synthesizing protein- polymer-drug conjugates. Side-chain reactive polymers are more chemically versatile than current linkers in use for ADCs, and can serve multiple functions to overcome current ADC limitations. We will functionalize polymer poly(PFPA) to enable conjugation to specific protein sites, and load releasable small molecules onto the polymer, using a range of drug loading ratios, with combinations of small molecules to enable combination therapy (Aim 2). We will measure and model cellular and tissue trafficking of the conjugates (Aim 3), a key consideration for therapeutic success. The overall objective of this application is to extend the capacity of scaffold proteins and side-chain reactive polymers to fill the gap in molecular targeting challenges. Our work will have a broader positive impact by establishing methods for synthesizing bioconjugates using a myriad of polypeptide folds and polymer linkers, towards the ultimate goal of creating targeted treatments for every patient who needs them.
项目总结/文摘

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Sarah J. Moore其他文献

Semi-field evaluation of freestanding transfluthrin passive emanators and the BG sentinel trap as a “push-pull control strategy” against Aedes aegypti mosquitoes
  • DOI:
    10.1186/s13071-020-04263-3
  • 发表时间:
    2020-07-31
  • 期刊:
  • 影响因子:
    3.500
  • 作者:
    Mgeni M. Tambwe;Sarah J. Moore;Hassan Chilumba;Johnson K. Swai;Jason D. Moore;Caleb Stica;Adam Saddler
  • 通讯作者:
    Adam Saddler
Estimating the hole surface area of insecticide-treated nets using image analysis, manual hole counting and exact hole measurements
  • DOI:
    10.1186/s12936-025-05324-7
  • 发表时间:
    2025-03-14
  • 期刊:
  • 影响因子:
    3.000
  • 作者:
    Emmanuel Mbuba;Natalia Mañas-Chavernas;Sarah J. Moore;Philipo David Ruzige;Dickson Kobe;Jason Moore;Rose Philipo;Noela Kisoka;Gianpaolo Pontiggia;Frank Chacky;Charles Dismasi Mwalimu;Philippe Claude Cattin;Julia Wolleb;Robin Sandkuehler;Amanda Ross
  • 通讯作者:
    Amanda Ross
A review of selective indoor residual spraying for malaria control
  • DOI:
    10.1186/s12936-024-05053-3
  • 发表时间:
    2024-08-23
  • 期刊:
  • 影响因子:
    3.000
  • 作者:
    Seth R. Irish;Derric Nimmo;Jameel Bharmel;Frederic Tripet;Pie Müller;Pablo Manrique-Saide;Sarah J. Moore
  • 通讯作者:
    Sarah J. Moore
Scalable camera traps for measuring the attractiveness of sugar baits for controlling malaria and dengue vectors
  • DOI:
    10.1186/s13071-024-06539-4
  • 发表时间:
    2024-12-03
  • 期刊:
  • 影响因子:
    3.500
  • 作者:
    Felician C. Meza;Frank C. Tenywa;Simon Ashall;Fredros O. Okumu;Sarah J. Moore;Frederic Tripet
  • 通讯作者:
    Frederic Tripet
Contrasting vector competence of three main East African Anopheles malaria vector mosquitoes for Plasmodium falciparum
  • DOI:
    10.1038/s41598-025-86409-w
  • 发表时间:
    2025-01-17
  • 期刊:
  • 影响因子:
    3.900
  • 作者:
    Prisca A. Kweyamba;Lorenz M. Hofer;Ummi A. Kibondo;Rehema Y. Mwanga;Rajabu M. Sayi;Fatuma Matwewe;Dickson W. Lwetoijera;Mgeni M. Tambwe;Sarah J. Moore
  • 通讯作者:
    Sarah J. Moore

Sarah J. Moore的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Sarah J. Moore', 18)}}的其他基金

Engineering therapeutic and diagnostic proteins for tumor biomarker mesothelin
工程治疗和诊断肿瘤生物标志物间皮素蛋白
  • 批准号:
    8955792
  • 财政年份:
    2015
  • 资助金额:
    $ 39.88万
  • 项目类别:

相似海外基金

Double Incorporation of Non-Canonical Amino Acids in an Animal and its Application for Precise and Independent Optical Control of Two Target Genes
动物体内非规范氨基酸的双重掺入及其在两个靶基因精确独立光学控制中的应用
  • 批准号:
    BB/Y006380/1
  • 财政年份:
    2024
  • 资助金额:
    $ 39.88万
  • 项目类别:
    Research Grant
Quantifying L-amino acids in Ryugu to constrain the source of L-amino acids in life on Earth
量化 Ryugu 中的 L-氨基酸以限制地球生命中 L-氨基酸的来源
  • 批准号:
    24K17112
  • 财政年份:
    2024
  • 资助金额:
    $ 39.88万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Collaborative Research: RUI: Elucidating Design Rules for non-NRPS Incorporation of Amino Acids on Polyketide Scaffolds
合作研究:RUI:阐明聚酮化合物支架上非 NRPS 氨基酸掺入的设计规则
  • 批准号:
    2300890
  • 财政年份:
    2023
  • 资助金额:
    $ 39.88万
  • 项目类别:
    Continuing Grant
Basic research toward therapeutic strategies for stress-induced chronic pain with non-natural amino acids
非天然氨基酸治疗应激性慢性疼痛策略的基础研究
  • 批准号:
    23K06918
  • 财政年份:
    2023
  • 资助金额:
    $ 39.88万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Molecular mechanisms how arrestins that modulate localization of glucose transporters are phosphorylated in response to amino acids
调节葡萄糖转运蛋白定位的抑制蛋白如何响应氨基酸而被磷酸化的分子机制
  • 批准号:
    23K05758
  • 财政年份:
    2023
  • 资助金额:
    $ 39.88万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Molecular recognition and enantioselective reaction of amino acids
氨基酸的分子识别和对映选择性反应
  • 批准号:
    23K04668
  • 财政年份:
    2023
  • 资助金额:
    $ 39.88万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Design and Synthesis of Fluorescent Amino Acids: Novel Tools for Biological Imaging
荧光氨基酸的设计与合成:生物成像的新工具
  • 批准号:
    2888395
  • 财政年份:
    2023
  • 资助金额:
    $ 39.88万
  • 项目类别:
    Studentship
Structurally engineered N-acyl amino acids for the treatment of NASH
用于治疗 NASH 的结构工程 N-酰基氨基酸
  • 批准号:
    10761044
  • 财政年份:
    2023
  • 资助金额:
    $ 39.88万
  • 项目类别:
Lifestyle, branched-chain amino acids, and cardiovascular risk factors: a randomized trial
生活方式、支链氨基酸和心血管危险因素:一项随机试验
  • 批准号:
    10728925
  • 财政年份:
    2023
  • 资助金额:
    $ 39.88万
  • 项目类别:
Single-molecule protein sequencing by barcoding of N-terminal amino acids
通过 N 端氨基酸条形码进行单分子蛋白质测序
  • 批准号:
    10757309
  • 财政年份:
    2023
  • 资助金额:
    $ 39.88万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了