Systematic evaluation of the effect of different apolipoprotein A-I mimetic peptides on the performance of synthetic high-density lipoproteins in vitro and in vivo

Yuan, Wenjie; Ernst, Kelsey; Kuai, Rui; Morin, Emily E.; Yu, Minzhi; Sviridov, Denis; Tang, Jie; Mei, Ling; Li, Dan; Ackermann, Rose; Remaley, Alan T.; Schwendeman, Anna

doi:10.1016/j.nano.2022.102646

Cited by 6 publications

(3 citation statements)

References 13 publications

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“…We later explored the effect of a kink with a more promising peptide (N3 system) and will return to apoE helix 6 results in that context. Although peptide helicity increases when it’s bound to a lipid bilayer [42], we will consider these helixes as poor binding for now.…”

Section: Resultsmentioning

confidence: 99%

Systematic Evaluation of Lecithin:Cholesterol Acyltransferase Binding Sites in Apolipoproteins via Peptide Based Nanodiscs: Regulatory Role of Charged Residues at Positions 4 and 7

Niemelä,

Koivuniemi

2023

Preprint

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Lecithin:cholesterol acyltransferase (LCAT) exhibits α-activity on high-density and β-activity on low-density lipoproteins. However, the molecular determinants governing LCAT activation by different apolipoproteins remain elusive. Uncovering these determinants would offer the opportunity to design and explore advanced therapies against dyslipidemias. Here, we have conducted coarse-grained and all-atom molecular dynamics simulations of LCAT with nanodiscs made with α-helical amphiphilic peptides either derived from apolipoproteins A1 and E (apoA1 and apoE) or apoA1 mimetic peptide 22A that was optimized to activate LCAT. This study aims to explore what drives the binding of peptides to our previously identified interaction site in LCAT. We hypothesized that this approach could be used to screen for binding sites of LCAT in different apolipoproteins and would provide insights to differently localized LCAT activities. Our screening approach was able to discriminate apoA1 helixes 4, 6, and 7 as key contributors to the interaction with LCAT supporting the previous research data. The simulations provided detailed molecular determinants driving the interaction with LCAT: the formation of hydrogen bonds or salt bridges between peptides E4 or D4 and LCAT S236 or K238 residues. Additionally, salt bridging between R7 and D73 was observed, depending on the availability of R7. Expanding our investigation to diverse plasma proteins, we detected novel LCAT binding helixes in apoL1, apoB100, and serum amyloid A. Our findings suggest that the same binding determinants, involving E4 or D4 -S236 and R7-D73 interactions, influence LCAT β-activity on low-density lipoproteins, where apoE and or apoB100 are hypothesized to interact with LCAT.

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Section: Resultsmentioning

confidence: 99%

Systematic Evaluation of Lecithin:Cholesterol Acyltransferase Binding Sites in Apolipoproteins via Peptide Based Nanodiscs: Regulatory Role of Charged Residues at Positions 4 and 7

Niemelä,

Koivuniemi

2023

Preprint

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“…sHDLs composed of 22A, POPC, and POPS were prepared by the lyophilization–rehydration method as described previously. , 22A and POPC were dissolved and mixed in acetic acid in a lipid-to-peptide weight ratio of 2:1. For POPS-containing sHDLs, 5, 10, 25, or 50% of POPC (mass ratio) was replaced by POPS-Na during preparation.…”

Section: Methodsmentioning

confidence: 99%

Enhancement of Anti-inflammatory Effects of Synthetic High-Density Lipoproteins by Incorporation of Anionic Lipids

Yu,

Dorsey,

Halseth

et al. 2023

Mol. Pharmaceutics

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Phosphatidylserine (PS) is an anionic phospholipid component in endogenous high-density lipoprotein (HDL). With the intrinsic anti-inflammatory effects of PS and the correlation between PS content and HDL functions, it was hypothesized that incorporating PS would enhance the therapeutic effects of HDL mimetic particles. To test this hypothesis, a series of synthetic highdensity lipoproteins (sHDLs) were prepared with an apolipoprotein A-I (ApoA-1) mimetic peptide, 1-palmitoyl-2-oleoyl-glycero-3phosphocholine (POPC), and 1-palmitoyl-2-oleoyl-glycero-3-phospho-L-serine (POPS). Incorporating PS was found to improve the particle stability of sHDLs. Moreover, increasing the PS content in sHDLs enhanced the anti-inflammatory effects on lipopolysaccharide-activated macrophages and endothelial cells. The incorporation of PS had no negative impact on cholesterol efflux capacity, in vivo cholesterol mobilization, and did not affect the pharmacokinetic profiles of sHDLs. Such results suggest the therapeutic potential of PS-containing sHDLs for inflammation resolution in atherosclerosis and other inflammatory diseases.

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“…This preparation was shown to greatly increase HDL-C levels in dyslipidemic patients (van Capelleveen et al, 2014). In a recent study, authors tested the ability to promote cholesterol efflux and esterification of 3 of these preparations and found that the mimetics with the highest capacity to promote both steps of RCT in vitro could no replicate those results in vivo (Yuan et al, 2023). These findings underscore the significance of both pharmacodynamics and pharmacokinetics in determining the effectiveness of rHDL formulations.…”

Section: Rna-based Therapymentioning

confidence: 99%

High density lipoprotein as a therapeutic target: Focus on its functionality

ROSSO,

DAVICO,

CHIAPPE

et al. 2023

BIOCELL

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Cardiovascular diseases (CVDs) are the leading cause of death globally. CVDs are a group of disorders of the heart and blood vessels and include coronary heart disease, cerebrovascular disease and rheumatic heart disease among other conditions. There are multiple independent risk factors for CVD, including hypertension, age, smoking, insulin resistance, elevated low-density lipoprotein cholesterol (LDL-C) levels, and triglyceride levels. LDL-C levels have traditionally been the target for therapies aimed at reducing CVD risk. High density lipoprotein (HDL) constitutes the only lipoprotein fraction with atheroprotective functions. Early HDL-targeted therapies have focused on increasing HDL-C levels. However, clinical trials have shown that raising HDL-C with niacin failed to achieve CVD reduction. A possible explanation for these findings is that these drugs could interfere with lipid metabolism and cause alterations in HDL structure and composition, leading to loss of functionality. As a result, targeting HDL-C levels would be insufficient to achieve CVD risk reduction, making HDL functionality a more desirable focus for HDL-directed therapies. There are several drugs which show the potential to improve HDL functionality. These drugs include molecules already approved for human use, such as statins and niacin, and particularly, compounds currently undergoing development such as apolipoprotein A-I mimetics and reconstituted HDL preparations. These therapies show promising potential to improve HDL functionality specifically. Future therapeutic strategies should incorporate HDL functionality as a main target of interest.

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Systematic evaluation of the effect of different apolipoprotein A-I mimetic peptides on the performance of synthetic high-density lipoproteins in vitro and in vivo

Cited by 6 publications

References 13 publications

Systematic Evaluation of Lecithin:Cholesterol Acyltransferase Binding Sites in Apolipoproteins via Peptide Based Nanodiscs: Regulatory Role of Charged Residues at Positions 4 and 7

Systematic Evaluation of Lecithin:Cholesterol Acyltransferase Binding Sites in Apolipoproteins via Peptide Based Nanodiscs: Regulatory Role of Charged Residues at Positions 4 and 7

Enhancement of Anti-inflammatory Effects of Synthetic High-Density Lipoproteins by Incorporation of Anionic Lipids

High density lipoprotein as a therapeutic target: Focus on its functionality

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