Application of a novel coumarin-derivative near-infrared fluorescence probe to amyloid-β imaging and inhibition in Alzheimer's disease

Fibrillar protein aggregates are characteristic of neurodegenerative diseases but represent difficult targets for ligand design, because limited structural information about the binding sites is available. Ligand-based virtual screening has been used to develop a computational method for the selection of new ligands for Aβ(1–42) fibrils, and five new ligands have been experimentally confirmed as nanomolar affinity binders. A database of ligands for Aβ(1–42) fibrils was assembled from the literature and used to train models for the prediction of dissociation constants based on chemical structure. The virtual screening pipeline consists of three steps: a molecular property filter based on charge, molecular weight, and logP; a machine learning model based on simple chemical descriptors; and machine learning models that use field points as a 3D description of shape and surface properties in the Forge software. The three-step pipeline was used to virtually screen 698 million compounds from the ZINC15 database. From the top 100 compounds with the highest predicted affinities, 46 compounds were experimentally investigated by using a thioflavin T fluorescence displacement assay. Five new Aβ(1–42) ligands with dissociation constants in the range 20–600 nM and novel structures were identified, demonstrating the power of this ligand-based approach for discovering new structurally unique, high-affinity amyloid ligands. The experimental hit rate using this virtual screening approach was 10.9%.

show abstract

“…We first compiled a data set of experimentally determined dissociation constants for ligand binding to Aβ(1–42) fibrils. − ...…”

Section: Resultsmentioning

confidence: 99%

Discovery of High-Affinity Amyloid Ligands Using a Ligand-Based Virtual Screening Pipeline

2023

View full text Add to dashboard Cite

show abstract

“…Coumarins, also known as benzopyran-2-ones, have a large range of biological applications 46). 102 These two amphiphilic probes contain a lipophilic conjugated thiophenebridged unit as the EDG and Aβ recognition group, an aminomodified benzofuran group as the EWG, and a vinyl moiety between both groups to extend the conjugated system (Figure 46). Regarding the native photophysical properties, compounds 78 and 79 exhibited absorption wavelengths at 457 and 474 nm and emission wavelengths at 690 and 578 nm, respectively; compound 79 exhibited a quantum yield of 0.748, higher than that of compound 78 (φ = 0.057).…”

Section: ■ the "Theranostic" Approach In Admentioning

confidence: 99%

“… 101 Based on the D-π-A architecture, Pan et al designed two novel fluorescence imaging probes for Aβ, compounds 78 and 79 (CouS-1 and CouS-4, respectively, in the original paper) ( Figure 46 ). 102 These two amphiphilic probes contain a lipophilic conjugated thiophene-bridged unit as the EDG and Aβ recognition group, an amino-modified benzofuran group as the EWG, and a vinyl moiety between both groups to extend the conjugated system ( Figure 46 ).…”

Section: Amyloid-β Targeting Theranosticsmentioning

confidence: 99%

See 1 more Smart Citation

Recent Advances in Fluorescent Theranostics for Alzheimer’s Disease: A Comprehensive Survey on Design, Synthesis, and Properties

Francisco,

Malafaia,

Melo

et al. 2024

ACS Omega

View full text Add to dashboard Cite

Alzheimer's disease (AD) is the most common form of neurodegenerative dementia that is rapidly becoming a major health problem, especially in developed countries because of their increasing life expectancy. Two main problems are often associated with the disease: (i) the absence of a widely accessible "gold-standard" for early diagnosis and (ii) lack of effective therapies with disease-modifying effects. The recent success of the monoclonal antibody lecanemab played an important role not only in clarifying a possible druggable pathway but also in spelling the revival of small molecule drug discovery. Unlike bulky biologics, small molecules are structurally less complex, generally cheaper, and compatible with at-home oral consumption, making it feasible for people to start their drug regimen early and stay on it longer. In this sense, small-molecule near-infrared fluorescent theranostics have been gaining more and more attention from the scientific community, as they have the potential to simultaneously provide diagnostic outputs and deliver therapeutic action, paving the way toward personalized medicine in AD patients. They also have the potential to shift the diagnostic "status-quo" from expensive and limited-access PET radiotracers toward inexpensive and handy imaging tools widely available for primary patient screening and preclinical animal studies. Herein, we review the most recent advances in the field of fluorescent theranostics for Alzheimer's disease, detailing their design strategies, synthetic approaches and imaging and therapeutic properties in vitro and in vivo. With this Review, we intend to provide a milestone in the acquired knowledge in the field of AD theranostics, encouraging the future development of properly designed theranostic compounds with improved chances to reach clinical applications.

show abstract

“…We compiled a database of 3457 measurements of ligand–amyloid fibril interactions from the scientific literature. 50–385 The requirements to be included in this database were (1) a known chemical structure, (2) a structure that does not contain metals (metalloligands have been thoroughly reviewed elsewhere in the literature 43,386–391 ), (3) a K d or IC 50 measurement, and (4) a fibril target related to Aβ, tau, or αSyn. Nearly half of the database reports on binding to Aβ fibrils formed in vitro , although recent years has seen a shift in focus toward tau and αSyn fibrils formed in vitro (Table 1).…”

Section: Introductionmentioning

confidence: 99%

A closer look at amyloid ligands, and what they tell us about protein aggregates

Chisholm,

Hunter

2024

Chem. Soc. Rev.

View full text Add to dashboard Cite

show abstract

Application of a novel coumarin-derivative near-infrared fluorescence probe to amyloid-β imaging and inhibition in Alzheimer's disease

Cited by 8 publications

References 25 publications

Discovery of High-Affinity Amyloid Ligands Using a Ligand-Based Virtual Screening Pipeline

Discovery of High-Affinity Amyloid Ligands Using a Ligand-Based Virtual Screening Pipeline

Recent Advances in Fluorescent Theranostics for Alzheimer’s Disease: A Comprehensive Survey on Design, Synthesis, and Properties

A closer look at amyloid ligands, and what they tell us about protein aggregates

Contact Info

Product

Resources

About