1 research outputs found
Development of Innovative Antiatherosclerotic Peptides through the Combination of Molecular Modeling and a Dual (BiochemicalâCellular) Screening System
Cardiovascular disease (CVD) is a leading cause of death worldwide. Approximately 60% of patients treated with lowâdensity lipoprotein (LDL)âlowering drug treatments, with onâtarget plasma cholesterol levels, are still suffering clinical acute ischemic events. Mechanisms, such as LDL aggregation, underlie extracellular and intracellular cholesterol accumulation in the vasculature. A peptide sequence (P3) of the lowâdensity lipoprotein receptorârelated protein 1 (LRP1) efficiently protects LDL from sphingomyelinase (SMaseâ) and phospholipase A2 (PLA2)âinduced LDL aggregation. The aim is to design families of peptide derivatives from P3 with enhanced potency and proteolytic stability. New peptides are designed through in silico conformational sampling and ApoBâ100 molecular docking, and are tested in dual (biochemicalâcellular) screening assays. A total of 46 new peptides including linear, fragment, cyclic, and alanine scanning derivatives are generated through two consecutive optimization rounds. Structurally and functionally optimized peptides contain hotspot residues that are replaced by alanine. This strategy confers an increased capacity to form prone alphaâhelix conformations crucial for the electrostatic interaction with ApoBâ100. These new compounds are highly efficient at inhibiting LDL aggregation and human coronary vascular smooth muscle cellâcholesteryl ester loading and should be studied in preclinical models of atherosclerosis.Cardiovascular disease (CVD) is a leading cause of death worldwide. Approximately 60% of patients treated with lowâdensity lipoprotein (LDL)âlowering drug treatments, with onâtarget plasma cholesterol levels, are still suffering clinical acute ischemic events. Mechanisms, such as LDL aggregation, underlie extracellular and intracellular cholesterol accumulation in the vasculature. A peptide sequence (P3) of the lowâdensity lipoprotein receptorârelated protein 1 (LRP1) efficiently protects LDL from sphingomyelinase (SMaseâ) and phospholipase A2 (PLA2)âinduced LDL aggregation. The aim is to design families of peptide derivatives from P3 with enhanced potency and proteolytic stability. New peptides are designed through in silico conformational sampling and ApoBâ100 molecular docking, and are tested in dual (biochemicalâcellular) screening assays. A total of 46 new peptides including linear, fragment, cyclic, and alanine scanning derivatives are generated through two consecutive optimization rounds. Structurally and functionally optimized peptides contain hotspot residues that are replaced by alanine. This strategy confers an increased capacity to form prone alphaâhelix conformations crucial for the electrostatic interaction with ApoBâ100. These new compounds are highly efficient at inhibiting LDL aggregation and human coronary vascular smooth muscle cellâcholesteryl ester loading and should be studied in preclinical models of atherosclerosis.A.B.-A. and C.P. contributed equally to this work. The authors thank Dr.
Ignasi Gich, Professor of Clinical Pharmacology and Therapeutics and
Researcher of Sant Pau Biomedical Research Institute (IIB-SantPau) and
CIBER EpidemiologĂa y Salud PĂșblica (CIBERESP), for this help in statistical
analysis and graph representations. The Ministry of Science and
Innovation of Spain, in the framework of the State Plan of Scientific
and Technical Innovation Investigation 2013â2016, awarded funding to
the project âDEVELOPMENT OF AN INNOVATIVE THERAPY FOR THE
TREATMENT OF THE ATHEROSCLEROSIS THROUGH INHIBITION OF
CHOLESTEROL VASCULAR ACCUMULATIONâ led by IPROTEOS SL with
File No. RTC-2016-5078-1. Support was also received from the FundaciĂł
MARATĂ TV3 Project 201521-10 (to VLl-C), and FIS PI18/01584 (to VLl-C)
from the Instituto de Salud Carlos III (ISCIII) and cofinanced with ERDFs.
Support was also received from Ministerio de EconomĂa y Competitividad
to DdG-C (IJCI-2016-29393). CIBER Enfermedades Cardiovasculares
(CIBERCV; CB16/1100403 (DdG-C, VLl-C) are projects run by the Instituto
de Salud Carlos III (ISCIII). The authors also acknowledge the support
from âSecretaria dâUniversitats i Recerca del Departament dâEconomia I
Coneixement de la Generalitat de Catalunyaâ (2017SGR946 to VLl-C).Peer reviewe