A screening platform based on epitope editing for drug discovery

Abstract

The interaction between an antibody and its epitope has been daily utilized in various biological studies; however it has been rarely explored whether small molecules can alter the interaction. We discovered that small molecules could alter/edit surface properties of amyloid beta (Aβ) epitopes, and consequently inhibit or enhance corresponding antibody recognition. Remarkably, this editing effect could generate functional changes including protein aggregation behaviors, cell cytokine secreting and in vivo microglia activation. According to this discovery, we proposed a screen 2 platform based on epitope editing for drug discovery (SPEED). With a small library of compounds, we validated that SPEED could be used to seek new leads for Aβ species.We also demonstrated that this platform could potentially be extended to other targets including tau protein and PD-L1 protein. The SPEED is a simple, fast and label-free screening method. We believe that the SPEED strategy could be universally applicable for seeking and validating drug candidates and imaging ligands.

β-Amyloid Peptides Manipulate Switching Behaviors of Donor–Acceptor Stenhouse Adducts

“…Recently, our group demonstrated that small molecules could alter epitope binding to its antibody, resulting in enhanced or weakened binding of the antibody to its antigen. We found that this epitope alteration could be used as a screening platform for the discovery of drug (we termed this s creening p latform based on e pitope alt e ration for d iscovery as SPEED) . To investigate whether SHA-2 has this alteration effect, we incubated Aβ40 monomers with and without SHA-2, and Aβ40 antibody 4G8, whose binding epitope is the hydrophobic Leu17–Val24 segment, was used in our dot-blotting assay.…”

“…We found that this epitope alteration could be used as a screening platform for the discovery of drug (we termed this screening platform based on epitope alteration for discovery as SPEED). 52 To investigate whether SHA-2 has this alteration effect, we incubated Aβ40 monomers with and without SHA-2, and Aβ40 antibody 4G8, whose binding epitope is the hydrophobic Leu17−Val24 segment, was used in our dot-blotting assay. From Figure 3a, it is clear that SHA-2 can significantly weaken the binding between Aβ40 and 4G8 antibody, suggesting that SHA-2 can bind to the hydrophobic environment in Aβ40 peptides.…”

β-Amyloid peptides tailor switching behaviors of Donor-Acceptor Stenhouse Adducts

“…Recently, our group demonstrated that small molecules could alter epitope binding to its antibody, resulting enhanced or weakened binding of the antibody to its antigen. 40 To investigate whether SHA-2 has this alteration effect, we incubated Aβ monomers with and without SHA-2, and Aβ antibody 4G8 (epitope Leu17-Val24) was used in our dot-blotting assay. From Fig.3a, it is clear that SHA-2 can significantly weaken the binding between Aβ and 4G8 antibody, suggesting that SHA-2 can bind to Aβ peptides.…”