TY - JOUR
T1 - Targeting transthyretin in Alzheimer's disease
T2 - Drug discovery of small-molecule chaperones as disease-modifying drug candidates for Alzheimer's disease
AU - Cotrina, Ellen Y.
AU - Santos, Luis Miguel
AU - Rivas, Josep
AU - Blasi, Daniel
AU - Leite, José Pedro
AU - Liz, Márcia A.
AU - Busquets, Maria Antònia
AU - Planas, Antoni
AU - Prohens, Rafel
AU - Gimeno, Ana
AU - Jiménez-Barbero, Jesús
AU - Gales, Luis
AU - Llop, Jordi
AU - Quintana, Jordi
AU - Cardoso, Isabel
AU - Arsequell, Gemma
N1 - Funding Information:
The work was supported by a grant from the Fundació Marató de TV3 (neurodegenerative diseases call, project reference: 20140330-31-32-33-34, http://www.ccma.cat/tv3/marato/en/projectes-financats/2013/212/ ). The group at IBMC-i3S also acknowledges for funding through grant Norte-01-0145-FEDER-000008 -Porto Neurosciences and Neurologic Disease Research Initiative at i3S, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (FEDER).
Funding Information:
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.
Funding Information:
Furthermore, Isothermal Titration Calorimetry (ITC) technique has been used to corroborate the chaperoning effect of five of the best small-molecule compounds as described previously [27]. Thus, we have compared the binding in the A?(12?28)/TTR/SMC ternary complexes with the binary interaction A?(12?28)/TTR (Figs. S12 and S13 at the Supporting Information). In addition, a full thermodynamic characterization of the ternary complexes with A?(1?40) and TTR and each of the five best selected SMCs was obtained (Fig. 6). The binary TTR/A?(1?40) (1:1) complex formation shows a dissociation constant of Kd = 6.49 ?M. However, IDIF enhances this interaction between TTR and A?(1?40), since the Kd is reduced to 3.34 ?M when TTR in the presence of IDIF is titrated with A?(1?40). Similar improvements were observed for the ternary complexes with the best SMCs (i.e. Kd = 1.52 ?M (LUT); 3.42 ?M (SUL); 0.81 ?M (OLS) and 2.34 ?M (FLU)).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 Fundaci? La Marat? 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 Fundaci? Marat? de TV3 (Spain) and a contract from Ford Espa?a - Fundaci?n 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.
Publisher Copyright:
© 2021 Elsevier Masson SAS
PY - 2021/12/15
Y1 - 2021/12/15
N2 - 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.
AB - 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.
KW - AD disease-modifying drugs
KW - Alzheimer's disease (AD)
KW - Alzheimer's disease drug discovery
KW - Aβ interaction
KW - Computational screening
KW - HTS screening
KW - Multi-target screening
KW - Protein-protein interactions
KW - Repurposing
KW - Small molecule chaperones (SMCs)
KW - Targeting transthyretin
KW - Transthyretin
KW - Transthyretin tetramer stability
UR - http://www.scopus.com/inward/record.url?scp=85115196147&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2021.113847
DO - 10.1016/j.ejmech.2021.113847
M3 - Article
C2 - 34555615
AN - SCOPUS:85115196147
SN - 0223-5234
VL - 226
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
M1 - 113847
ER -