SAR by kinetics for drug discovery in protein misfolding diseases

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SAR by kinetics for drug discovery in protein misfolding diseases. / Chia, Sean; Habchi, Johnny; Michaels, Thomas C.T.; Cohen, Samuel I.A.; Linse, Sara; Dobson, Christopher M.; Knowles, Tuomas P.J.; Vendruscolo, Michele.

I: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, Nr. 41, 2018, s. 10245-10250.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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Chia, S, Habchi, J, Michaels, TCT, Cohen, SIA, Linse, S, Dobson, CM, Knowles, TPJ & Vendruscolo, M 2018, 'SAR by kinetics for drug discovery in protein misfolding diseases', Proceedings of the National Academy of Sciences of the United States of America, vol. 115, nr. 41, s. 10245-10250. https://doi.org/10.1073/pnas.1807884115

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Chia, Sean ; Habchi, Johnny ; Michaels, Thomas C.T. ; Cohen, Samuel I.A. ; Linse, Sara ; Dobson, Christopher M. ; Knowles, Tuomas P.J. ; Vendruscolo, Michele. / SAR by kinetics for drug discovery in protein misfolding diseases. I: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, Nr. 41. s. 10245-10250.

RIS

TY - JOUR

T1 - SAR by kinetics for drug discovery in protein misfolding diseases

AU - Chia, Sean

AU - Habchi, Johnny

AU - Michaels, Thomas C.T.

AU - Cohen, Samuel I.A.

AU - Linse, Sara

AU - Dobson, Christopher M.

AU - Knowles, Tuomas P.J.

AU - Vendruscolo, Michele

PY - 2018

Y1 - 2018

N2 - To develop effective therapeutic strategies for protein misfolding diseases, a promising route is to identify compounds that inhibit the formation of protein oligomers. To achieve this goal, we report a structure.activity relationship (SAR) approach based on chemical kinetics to estimate quantitatively how small molecules modify the reactive flux toward oligomers. We use this estimate to derive chemical rules in the case of the amyloid beta peptide (Aβ), which we then exploit to optimize starting compounds to curtail Aâ oligomer formation. We demonstrate this approach by converting an inactive rhodanine compound into an effective inhibitor of Aβ oligomer formation by generating chemical derivatives in a systematic manner. These results provide an initial demonstration of the potential of drug discovery strategies based on targeting directly the production of protein oligomers.

AB - To develop effective therapeutic strategies for protein misfolding diseases, a promising route is to identify compounds that inhibit the formation of protein oligomers. To achieve this goal, we report a structure.activity relationship (SAR) approach based on chemical kinetics to estimate quantitatively how small molecules modify the reactive flux toward oligomers. We use this estimate to derive chemical rules in the case of the amyloid beta peptide (Aβ), which we then exploit to optimize starting compounds to curtail Aâ oligomer formation. We demonstrate this approach by converting an inactive rhodanine compound into an effective inhibitor of Aβ oligomer formation by generating chemical derivatives in a systematic manner. These results provide an initial demonstration of the potential of drug discovery strategies based on targeting directly the production of protein oligomers.

KW - Alzheimer's disease

KW - Amyloid beta peptide

KW - Chemical kinetics

KW - Protein aggregation

KW - Protein misfolding

U2 - 10.1073/pnas.1807884115

DO - 10.1073/pnas.1807884115

M3 - Article

VL - 115

SP - 10245

EP - 10250

JO - Proceedings of the National Academy of Sciences

T2 - Proceedings of the National Academy of Sciences

JF - Proceedings of the National Academy of Sciences

SN - 1091-6490

IS - 41

ER -