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De-risking Drug Discovery of Intracellular Targeting Peptides: Screening Strategies to Eliminate False-Positive Hits
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-05-01 , DOI: 10.1021/acsmedchemlett.0c00022 Simon Ng 1 , Yu-Chi Juang 1 , Arun Chandramohan 1 , Hung Yi Kristal Kaan 1 , Ahmad Sadruddin 1 , Tsz Ying Yuen 2 , Fernando J Ferrer-Gago 3 , Xue'Er Cheryl Lee 2 , Xi Liew 2 , Charles W Johannes 3 , Christopher J Brown 3 , Srinivasaraghavan Kannan 4 , Pietro G Aronica 4 , Nils A Berglund 4 , Chandra S Verma 4 , Lijuan Liu 5 , Alexander Stoeck 5 , Tomi K Sawyer 5 , Anthony W Partridge 1 , David P Lane 3
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-05-01 , DOI: 10.1021/acsmedchemlett.0c00022 Simon Ng 1 , Yu-Chi Juang 1 , Arun Chandramohan 1 , Hung Yi Kristal Kaan 1 , Ahmad Sadruddin 1 , Tsz Ying Yuen 2 , Fernando J Ferrer-Gago 3 , Xue'Er Cheryl Lee 2 , Xi Liew 2 , Charles W Johannes 3 , Christopher J Brown 3 , Srinivasaraghavan Kannan 4 , Pietro G Aronica 4 , Nils A Berglund 4 , Chandra S Verma 4 , Lijuan Liu 5 , Alexander Stoeck 5 , Tomi K Sawyer 5 , Anthony W Partridge 1 , David P Lane 3
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Nonspecific promiscuous compounds can mislead researchers and waste significant resources. This phenomenon, though well-documented for small molecules, has not been widely explored for the peptide modality. Here we demonstrate that two purported peptide-based KRas inhibitors, SAH-SOS1A and cyclorasin 9A5, exemplify false-positive molecules—in terms of both their binding affinities and cellular activities. Through multiple gold-standard biophysical techniques, we unambiguously show that both peptides lack specific binding to KRas and instead induce protein unfolding. Although these peptides inhibited cellular proliferation, the activities appeared to be off-target on the basis of a counterscreen with KRas-independent cell lines. We further demonstrate that their cellular activities are derived from membrane disruption. Accordingly, we propose that to de-risk false-positive molecules, orthogonal binding assays and cellular counterscreens are indispensable.
中文翻译：
降低细胞内靶向肽的药物发现风险：消除假阳性的筛选策略
非特异性混杂化合物会误导研究人员并浪费大量资源。这种现象虽然在小分子中有充分的记录，但尚未针对肽模式进行广泛探索。在这里，我们证明了两种声称的基于肽的 KRas 抑制剂 SAH-SOS1 A和环草素 9A5 是假阳性分子的例证——就其结合亲和力和细胞活性而言。通过多种黄金标准生物物理技术，我们明确表明两种肽都缺乏与 KRas 的特异性结合，而是诱导蛋白质解折叠。尽管这些肽抑制了细胞增殖，但根据 KRas 非依赖性细胞系的反筛选，这些活性似乎是脱靶的。我们进一步证明它们的细胞活动来自膜破坏。因此，我们建议为了降低假阳性分子的风险，正交结合试验和细胞计数器筛选是必不可少的。
更新日期：2020-05-01
中文翻译：
降低细胞内靶向肽的药物发现风险：消除假阳性的筛选策略
非特异性混杂化合物会误导研究人员并浪费大量资源。这种现象虽然在小分子中有充分的记录，但尚未针对肽模式进行广泛探索。在这里，我们证明了两种声称的基于肽的 KRas 抑制剂 SAH-SOS1 A和环草素 9A5 是假阳性分子的例证——就其结合亲和力和细胞活性而言。通过多种黄金标准生物物理技术，我们明确表明两种肽都缺乏与 KRas 的特异性结合，而是诱导蛋白质解折叠。尽管这些肽抑制了细胞增殖，但根据 KRas 非依赖性细胞系的反筛选，这些活性似乎是脱靶的。我们进一步证明它们的细胞活动来自膜破坏。因此，我们建议为了降低假阳性分子的风险，正交结合试验和细胞计数器筛选是必不可少的。
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