Peptide-brush polymers (PBPs), wherein every side-chain of the polymers is peptidic, represent a new class of proteomimetic with unusually high proteolytic resistance while maintaining bioactivity. Here, we sought to determine the origin of this behavior and to assess its generality via a combined theory and experimental approach. A series of PBPs with various polymer backbone structures were prepared and examined for their proteolytic stability and bioactivity. We discovered that an increase in the hydrophobicity of the polymer backbones is predictive of an elevation in proteolytic stability of the side-chain peptides. Computer simulations, together with small-angle X-ray scattering (SAXS) analysis, revealed globular morphologies for these polymers, in which pendant peptides condense around hydrophobic synthetic polymer backbones driven by the hydrophobic effect. As the hydrophobicity of the polymer backbones increases, the extent of solvent exposure of peptide cleavage sites decreases, reducing their accessibility to proteolytic enzymes. This study provides insight into the important factors driving PBP aqueous-phase structures to behave as globular, synthetic polymer-based proteomimetics.
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http://dx.doi.org/10.1021/acscentsci.1c01149 | DOI Listing |
PLoS One
December 2024
Center of Medical and Bio-Allied Health Sciences Research (CMBHSR), Ajman University, Ajman, United Arab Emirates.
Alzheimer's disease (AD) is characterized by the aggregation of amyloid β (Aβ) peptides and the formation of plaques in the brain, primarily derived from the proteolytic degradation of amyloid precursor protein (APP). Cathepsin B (CatB) is a cysteine protease that plays a pivotal role in this process, making it a potential target for the development of anti-Alzheimer's therapies. Apart from AD, CatB is implicated in various physiological and pathological processes, including cancer.
View Article and Find Full Text PDFJ Med Chem
December 2024
Department of Chemistry─BMC, Uppsala University, Box 576, 75123 Uppsala, Sweden.
The discovery of cell permeable and orally bioavailable von Hippel-Lindau (VHL) proteolysis targeting chimeras (PROTACs) is challenging as their structures locates them at, or beyond, the outer limits of oral druggable space. We have designed a set of nine VHL PROTACs and found that the linker had a profound impact on passive cell permeability. Determination of the solution ensembles in a nonpolar solvent revealed that high permeability was correlated to the ability of the PROTACs to adopt folded conformations that have a low solvent accessible 3D polar surface area.
View Article and Find Full Text PDFMol Biol Rep
December 2024
Department of Cariology, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha Dental College and Hospitals, Saveetha University, Chennai, 600 077, India.
Nano bio-encapsulation of phyto-vaccines for cancer has marked a cutting-edge strategy that brings together nanotechnology with plant-derived vaccines to enhance cancer therapy. Phyto-vaccines, isolated from bioactive compounds found in plants called protein bodies, have been shown to potentially stimulate the immune system to recognise and destroy cancer cells. However, challenges such as poor stability, rapid degradation, and limited bioavailability in the body have hindered their clinical application.
View Article and Find Full Text PDFAdv Sci (Weinh)
December 2024
Anatomy and Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine Nursing and Health Sciences, University of Galway, Galway, H91 W2TY, Ireland.
Therapeutic proteins, the fastest growing class of pharmaceuticals, are subject to rapid proteolytic degradation in vivo, rendering them inactive. Sophisticated drug delivery systems that maintain protein stability, prolong therapeutic effects, and reduce administration frequency are urgently required. Herein, a mechanoresponsive hydrogel is developed contained within a soft robotic drug delivery (SRDD) device.
View Article and Find Full Text PDFJ Phys Chem B
December 2024
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, UP 208 016, India.
Hydrated deep eutectic solvents (DESs) are recognized for their potential in biocatalysis due to their tunability, biocompatibility, greenness, and ability to keep protein stable and active. However, the mechanisms governing enzyme stability and activity in DES remain poorly understood. Herein, using bromelain as the model enzyme and acetamide (0.
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