Centres Científics i Tecnològics UB

News

20.09.2021

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

PhD. Rafel Prohens, responsible of the Polymorphism and Calorimetry Unit of the CCiTUB, along with researchers of various institutions, have published the paper "Targeting transthyretin in Alzheimer's disease: Drug discovery of small-molecule chaperones as disease-modifying drug candidates for Alzheimer's disease" in the European Journal of Medicinal Chemistry.

The highlights of the article are:
• Transthyretin has a well-established role in neuroprotection in Alzheimers Disease
• Iododiflunisal is a chaperone of the Transthyretin/Aβ interaction
• We have discovered compounds with the same chaperoning activity as Iododiflunisal
• Among the chaperones we discovered three registered drugs that can be repurposed
• They will be used to validate Transthyretin as a new target in Alzheimer's disease

The summary of the article is:

"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."