Details

Autor(en) / Beteiligte

• Zhu, Biyue
• Yang, Jing
• Van, Richard
• Yang, Fan
• Yu, Yue
• Yu, Astra
• Ran, Kathleen
• Yin, Keyi
• Liang, Yingxia
• Shen, Xunuo
• Yin, Wei
• Choi, Se Hoon
• Lu, Ying
• Wang, Changning
• Shao, Yihan
• Shi, Liang
• Tanzi, Rudolph E
• Zhang, Can
• Cheng, Yan
• Zhang, Zhirong
• Ran, Chongzhao

Titel

Epitope alteration by small molecules and applications in drug discovery

Ist Teil von

• Chemical science (Cambridge), 2022-07, Vol.13 (27), p.814-8116

Ort / Verlag

Cambridge: Royal Society of Chemistry

Erscheinungsjahr

2022

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Small molecules and antibodies are normally considered separately in drug discovery, except in the case of covalent conjugates. We unexpectedly discovered several small molecules that could inhibit or enhance antibodyepitope interactions which opens new possibilities in drug discovery and therapeutic modulation of auto-antibodies. We first discovered a small molecule, CRANAD-17, that enhanced the binding of an antibody to amyloid beta (A), one of the major hallmarks of Alzheimer's disease, by stable triplex formation. Next, we found several small molecules that altered antibodyepitope interactions of tau and PD-L1 proteins, demonstrating the generality of this phenomenon. We report a new screening technology for ligand discovery, screening platform based on epitope alteration for drug discovery (SPEED), which is label-free for both the antibody and small molecule. SPEED, applied to an A antibody, led to the discovery of a small molecule, GNF5837, that inhibits A aggregation and another, obatoclax, that binds A plaques and can serve as a fluorescent reporter in brain slices of AD mice. We also found a small molecule that altered the binding between A and auto-antibodies from AD patient serum. SPEED reveals the sensitivity of antibodyepitope interactions to perturbation by small molecules and will have multiple applications in biotechnology and drug discovery. A screening platform based on epitope alteration for drug discovery (SPEED).