Targeting transthyretin in Alzheimer's disease: Drug discovery of small-molecule chaperones as disease-modifying drug candidates for Alzheimer's disease

Transthyretin (TTR) has a well-established role in neuroprotection in Alzheimer's Disease (AD). We have setup a drug discovery program of small-molecule compounds that act as chaperones enhancing TTR/Amyloid-beta peptide (Aβ) interactions. A combination of computational drug repurposing approaches and in vitro biological assays have resulted in a set of molecules which were then screened with our in-house validated high-throughput screening ternary test. A prioritized list of chaperones was obtained and corroborated with ITC studies. Small-molecule chaperones have been discovered, among them our lead compound Iododiflunisal (IDIF), a molecule in the discovery phase; one investigational drug (luteolin); and 3 marketed drugs (sulindac, olsalazine and flufenamic), which could be directly repurposed or repositioned for clinical use. Not all TTR tetramer stabilizers behave as chaperones in vitro. These chemically diverse chaperones will be used for validating TTR as a target in vivo, and to select one repurposed drug as a candidate to enter clinical trials as AD disease-modifying drug.
I. Cardoso works under the Investigator FCT Program which is financed by national funds through FCT and co-financed by ESF through HPOP, type 4.2 - Promotion of Scientific Employment. M. Alemi was a recipient of a Research Fellowship (BIM) funded by the project of Fundació La Marató de TV3 (Spain), and L. M. Santos was a recipient of a fellowship from Norte 2020. J.P. Leite acknowledges the FCT fellowship SFRH/BD/129921/2017 (Portugal). IQAC-CSIC acknowledges a contract to Ellen Y. Cotrina funded by the project of Fundació Marató de TV3 (Spain) and a contract from Ford España - Fundación Apadrina la Ciencia (Spain). The group at CIC bioGUNE also acknowledges MINECO (Spain) for funding through grant CTQ2015-64597-C2-1-P and a Juan de la Cierva contract to A. Gimeno. We thank access to ALBA (XALOC), ESRF (ID30B) and Soleil (PROXIMA 1 and 2a) synchrotrons.