The ReFRAME library as a comprehensive drug repurposing library and its application to the treatment of cryptosporidiosis.
The ReFRAME library as a comprehensive drug repurposing library and its application to the treatment of cryptosporidiosis.
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DOI：
10.1073/pnas.1810137115
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发表时间：
2018-10-16
影响因子：
11.1
通讯作者：
Chatterjee AK
中科院分区：
文献类型：
--
作者：
Janes J;Young ME;Chen E;Rogers NH;Burgstaller-Muehlbacher S;Hughes LD;Love MS;Hull MV;Kuhen KL;Woods AK;Joseph SB;Petrassi HM;McNamara CW;Tremblay MS;Su AI;Schultz PG;Chatterjee AK
包含12000种化合物的ReFRAME化合物库是一个一流的药物再利用库，几乎涵盖了所有已进入临床开发阶段或经过重要临床前分析的小分子。建立这样一个筛选库的目的是能够在新的适应症（如被忽视的疾病或罕见病）中快速测试已证明安全性的化合物，因为在这些疾病领域，昂贵的研发商业动力较小。在开放获取平台上为学术和非营利性研究团体提供高价值的化合物库及相关筛选数据，应该能为生物医学研究提供新的工具化合物，并加速旨在为各种未满足的医疗需求开发新疗法的药物发现和/或开发项目。
先前在人体中测试过的药物的化学多样性和已知的安全性特征，使其成为一组有价值的化合物，可用于探索在其最初针对的适应症之外的潜在治疗用途，尤其是被忽视的热带疾病。这种“药物再利用”的做法在学术和其他非营利性药物发现工作中已经很常见，其吸引力在于将候选药物推进到临床所需的时间和资源大大减少。在此，我们报道了一个全面的开放获取的药物再定位筛选集合，包含12000种化合物（称为ReFRAME；再利用、重点挽救和加速药物化学），它是通过结合三个广泛使用的商业药物竞争情报数据库（科睿唯安Integrity、GVK Excelra GoStar和Citeline Pharmaprojects），以及对已在人体中使用剂量的小分子进行大量专利挖掘而组建的。到目前为止，已经购买或合成了12000种化合物（约占数据挖掘确定的化合物的80%），并随后进行铺板用于筛选。为了证明其用途，该化合物库针对隐孢子虫属进行了筛选，隐孢子虫是发展中国家儿童腹泻的主要病因，并且鉴定出了两种先前在人体中针对其他治疗适应症进行过测试的活性化合物。根据现有的人体剂量，两种化合物VB - 201和ASP - 7962的一种结构相关类似物，随后在隐孢子虫感染的动物模型中被证明在临床相关剂量下是有效的。此外，还开发了一个开放获取的数据门户（https://reframedb.org）来分享ReFRAME筛选命中结果，以鼓励进一步的后续研究，并使ReFRAME筛选库的影响最大化。
The ReFRAME collection of 12,000 compounds is a best-in-class drug repurposing library containing nearly all small molecules that have reached clinical development or undergone significant preclinical profiling. The purpose of such a screening collection is to enable rapid testing of compounds with demonstrated safety profiles in new indications, such as neglected or rare diseases, where there is less commercial motivation for expensive research and development. Providing the academic and nonprofit research community access to a high-value compound collection and related screening data in an open-access platform should provide new tool compounds for biomedical research, as well as accelerate drug-discovery and/or development programs aimed at developing new therapies for diverse unmet medical needs. The chemical diversity and known safety profiles of drugs previously tested in humans make them a valuable set of compounds to explore potential therapeutic utility in indications outside those originally targeted, especially neglected tropical diseases. This practice of “drug repurposing” has become commonplace in academic and other nonprofit drug-discovery efforts, with the appeal that significantly less time and resources are required to advance a candidate into the clinic. Here, we report a comprehensive open-access, drug repositioning screening set of 12,000 compounds (termed ReFRAME; Repurposing, Focused Rescue, and Accelerated Medchem) that was assembled by combining three widely used commercial drug competitive intelligence databases (Clarivate Integrity, GVK Excelra GoStar, and Citeline Pharmaprojects), together with extensive patent mining of small molecules that have been dosed in humans. To date, 12,000 compounds (∼80% of compounds identified from data mining) have been purchased or synthesized and subsequently plated for screening. To exemplify its utility, this collection was screened against Cryptosporidium spp., a major cause of childhood diarrhea in the developing world, and two active compounds previously tested in humans for other therapeutic indications were identified. Both compounds, VB-201 and a structurally related analog of ASP-7962, were subsequently shown to be efficacious in animal models of Cryptosporidium infection at clinically relevant doses, based on available human doses. In addition, an open-access data portal (https://reframedb.org) has been developed to share ReFRAME screen hits to encourage additional follow-up and maximize the impact of the ReFRAME screening collection.
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影响因子：
168.9
作者：
Kotloff, Karen L.;Nataro, James P.;Levine, Myron M.
通讯作者：
Levine, Myron M.
影响因子：
64.8
作者：
Manjunatha UH;Vinayak S;Zambriski JA;Chao AT;Sy T;Noble CG;Bonamy GMC;Kondreddi RR;Zou B;Gedeck P;Brooks CF;Herbert GT;Sateriale A;Tandel J;Noh S;Lakshminarayana SB;Lim SH;Goodman LB;Bodenreider C;Feng G;Zhang L;Blasco F;Wagner J;Leong FJ;Striepen B;Diagana TT
通讯作者：
Diagana TT
影响因子：
8.6
作者：
O'Boyle NM;Banck M;James CA;Morley C;Vandermeersch T;Hutchison GR
通讯作者：
Hutchison GR
影响因子：
4
作者：
Hulverson, Matthew A.;Choi, Ryan;Van Voorhis, Wesley C.
通讯作者：
Van Voorhis, Wesley C.
影响因子：
6.4
作者：
Hulverson, Matthew A.;Vinayak, Sumiti;Ojo, Kayode K.
通讯作者：
Ojo, Kayode K.