Author response: Molecular basis for activation of lecithin:cholesterol acyltransferase by a compound that increases HDL cholesterol

ABSTRACTLecithin:cholesterol acyltransferase (LCAT) and LCAT-activating small molecules are being investigated as treatments for coronary heart disease (CHD) and familial LCAT deficiency (FLD). Herein we report the crystal structure of LCAT bound to a potent activator and an acyl intermediate-like inhibitor, thereby revealing an active conformation of LCAT and that the activator is bound exclusively to its membrane-binding domain (MBD). Functional studies indicate that the compound does not modulate the affinity of LCAT for HDL, but instead stabilizes residues in the MBD and likely facilitates channeling of substrates into the active site. By demonstrating that these activators increase the activity of an FLD variant, we show that compounds targeting the MBD have therapeutic potential. In addition, our data better define the acyl binding site of LCAT and pave the way for rational design of LCAT agonists and improved biotherapeutics for augmenting or restoring reverse cholesterol transport in CHD and FLD patients.

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Molecular basis for activation of lecithin:cholesterol acyltransferase by a compound that increases HDL cholesterol

eLife ◽

10.7554/elife.41604 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 14

Author(s):

Kelly A Manthei ◽

Shyh-Ming Yang ◽

Bolormaa Baljinnyam ◽

Louise Chang ◽

Alisa Glukhova ◽

...

Keyword(s):

Active Site ◽

Molecular Basis ◽

Rational Design ◽

Therapeutic Potential ◽

Hdl Cholesterol ◽

Cholesterol Transport ◽

Active Conformation ◽

Lecithin:Cholesterol Acyltransferase ◽

Functional Studies ◽

Lcat Deficiency

Lecithin:cholesterol acyltransferase (LCAT) and LCAT-activating compounds are being investigated as treatments for coronary heart disease (CHD) and familial LCAT deficiency (FLD). Herein we report the crystal structure of human LCAT in complex with a potent piperidinylpyrazolopyridine activator and an acyl intermediate-like inhibitor, revealing LCAT in an active conformation. Unlike other LCAT activators, the piperidinylpyrazolopyridine activator binds exclusively to the membrane-binding domain (MBD). Functional studies indicate that the compound does not modulate the affinity of LCAT for HDL, but instead stabilizes residues in the MBD and facilitates channeling of substrates into the active site. By demonstrating that these activators increase the activity of an FLD variant, we show that compounds targeting the MBD have therapeutic potential. Our data better define the substrate binding site of LCAT and pave the way for rational design of LCAT agonists and improved biotherapeutics for augmenting or restoring reverse cholesterol transport in CHD and FLD patients.

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Author response for "Neuron‐Glia interaction: Molecular basis of Alzheimer’s Disease and Applications of Neuroproteomics"

10.1111/ejn.14838/v2/response1 ◽

2020 ◽

Author(s):

Abdallah Mohammad Ibrahim ◽

Faheem Hyder Pottoo ◽

Ekta Singh Dahiya ◽

Firdos Alam Khan ◽

JB Senthil Kumar

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Basis ◽

Author Response

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Novel LCAT (Lecithin:Cholesterol Acyltransferase) Activator DS-8190a Prevents the Progression of Plaque Accumulation in Atherosclerosis Models

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.120.314516 ◽

2020 ◽

Author(s):

Masato Sasaki ◽

Mina Delawary ◽

Hidetaka Sakurai ◽

Hideki Kobayashi ◽

Naoki Nakao ◽

...

Keyword(s):

Small Molecule ◽

High Throughput Screening ◽

Affinity Purification ◽

Atherosclerotic Lesion ◽

Hdl Cholesterol ◽

Lecithin:Cholesterol Acyltransferase ◽

Lesion Area ◽

Acyltransferase Activity ◽

Hdl Function

Objective: Enhancement of LCAT (lecithin:cholesterol acyltransferase) activity has possibility to be beneficial for atherosclerosis. To evaluate this concept, we characterized our novel, orally administered, small-molecule LCAT activator DS-8190a, which was created from high-throughput screening and subsequent derivatization. We also focused on its mechanism of LCAT activation and the therapeutic activity with improvement of HDL (high-density lipoprotein) functionality. Approach and Results: DS-8190a activated human and cynomolgus monkey but not mouse LCAT enzymes in vitro. DS-8190a was orally administered to cynomolgus monkeys and dose dependently increased LCAT activity (ca. 2.1-fold in 3 mg/kg group on day 7), resulting in HDL cholesterol elevation without drastic changes of non-HDL cholesterol. Atheroprotective effects were then evaluated using Ldl-r KO × hLcat Tg mice fed a Western diet for 8 weeks. DS-8190a treatment achieved significant reduction of atherosclerotic lesion area (48.3% reduction in 10 mg/kg treatment group). Furthermore, we conducted reverse cholesterol transport study using Ldl-r KO × hLcat Tg mice intraperitoneally injected with J774A.1 cells loaded with [ 3 H]-cholesterol and confirmed significant increases of [ 3 H] count in plasma (1.4-fold) and feces (1.4-fold on day 2 and 1.5-fold on day3) in the DS-8190a–treated group. With regard to the molecular mechanism involved, direct binding of DS-8190a to human LCAT protein was confirmed by 2 different approaches: affinity purification by DS-8190a–immobilized beads and thermal shift assay. In addition, the candidate binding site of DS-8190a in human LCAT protein was identified by photoaffinity labeling. Conclusions: This study demonstrates the potential of DS-8190a as a novel therapeutic for atherosclerosis. This is also the first report describing that a small-molecule direct LCAT activator achieved HDL cholesterol elevation in monkey and reduction of atherosclerotic lesion area with enhanced HDL function in rodent.

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