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 - 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
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=pure_univeritat_ramon_llull&SrcAuth=WosAPI&KeyUT=WOS:000703119000030&DestLinkType=FullRecord&DestApp=WOS_CPL
UR - http://hdl.handle.net/20.500.14342/3640
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 -