Chiral and non-chiral assemblies from lipidated serine-based pseudopeptidic molecules

Bijesh, M. B.; Dheepthi, N. U.; Sapala, Appa Rao; Shandilya, Ashutosh; Khare, Kedar; Haridas, V.

doi:10.1039/c6me00009f

Cited by 8 publications

(3 citation statements)

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“…In another related study, a series of acyclic pseudopeptides based on serine was designed and synthesized. 49 These lipidated molecules showed fibrillary morphology. The acyclic molecules contain two serine units connected by an aryl spacer.…”

Section: For Vesicular Assemblymentioning

confidence: 99%

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Tailoring of Peptide Vesicles: A Bottom-Up Chemical Approach

Haridas

2021

Acc. Chem. Res.

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Conspectus Spherical ordering from small molecules is a subject of intense interest to chemists. The inherent capability of amphiphiles to assemble spontaneously is the unique feature of the evolutionary process of life. Self-assembly is prevalent in biology and has attracted the interest of scientists across several disciplines. This is because scientists have realized that nature has extensively used this inherent organizational power contained in the molecules. Judicious use of the self-assembly principle is the cornerstone of nature’s exotic assemblies. These exotic assemblies lead to unimaginable functions in biology that might not have been predicted from the monomer building blocks alone. Recently, a number of chemical systems that self-assemble in aqueous or organic solvents to form vesicles were reported. This account provides advances made from our laboratory toward designing and understanding the mechanism of formation of spherical vesicular assembly. A bottom-up approach for the de novo design of vesicles using nonlipidated molecular architecture will be a paradigm shift in vesicular research. Vesicles act as a protocell model for studying the origin and evolution of cellular life. They could also act as excellent model systems for studying the fusion of cells and membrane transport. Self-assembled vesicles have enormous potential for several applications such as drug and biomolecule delivery to cells and in materials science. These aspects along with the dynamic nature of vesicular assembly have attracted researchers to the study of spherical assemblies. The common belief was that the molecules that form vesicles must have one polar head and two hydrophobic tails. All attempts to synthesize vesicles are by mimicking nature’s strategy, which mainly involves the self-assembly of lipid amphiphiles through a bilayer-like arrangement. Pseudopeptide-based molecules with the ability to form vesicles have changed this long-standing notion. In addition to chemical and medical applications, these peptide vesicles could act as models for protocells, membrane fusion, and the study of the vesiculation mechanism. This Account highlights the progress made toward a heuristic approach to the de novo design of vesicles using pseudopeptides as building blocks. A large number of diverse classes of pseudopeptides showed vesicular assembly. Various acyclic and cyclic molecules were designed and synthesized that showed spherical vesicular assembly. Cystine-based macrocyclic peptides showed drug encapsulation and release. Polymersomes with unusual topology, self-assembling tripodal ligands, and molecules containing amino acids such as lysine, leucine, cystine, and serine were synthesized. The incorporation of a wide variety of amino acids in the vesicle-forming peptides could enhance their scope and applications. The mechanism of vesiculation was also investigated using these designer molecules.

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Section: For Vesicular Assemblymentioning

confidence: 99%

“…In another related study, a series of acyclic pseudopeptides based on serine was designed and synthesized . These lipidated molecules showed fibrillary morphology.…”

Section: Self-assembling Designer Pseudopeptides For Vesicular Assemblymentioning

confidence: 99%

Tailoring of Peptide Vesicles: A Bottom-Up Chemical Approach

Haridas

2021

Acc. Chem. Res.

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“…Arguably, the most promising candidates which fulfill these requirements are self-assembling short peptides. Peptides are well-known to possess intrinsic self-assembling tendencies, which have been demonstrated by the formation of a plethora of supramolecular nano/microstructures ranging from spheres, vesicles, ribbons, and toroids to nanobelts, nanotubes, and fibers . In addition, most of these peptidic assemblies are biocompatible in nature, as is evident from their successful usage for a variety of biomedical applications including tissue engineering, cell attachment, nerve regeneration, and stem cell differentiation .…”

Section: Introductionmentioning

confidence: 99%

Redox Sensitive Self-Assembling Dipeptide for Sustained Intracellular Drug Delivery

Dhawan¹,

Ghosh²,

Ravinder³

et al. 2019

Bioconjugate Chem.

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The rational design and synthesis of molecules with functional supramolecular assemblies continues to be a challenging endeavor. Self-assembled nano- and microstructures from natural building blocks are considered more appropriate for medical applications due to their biocompatible nature. We report for the first time a simple redox-responsive dipeptide that self-assembles to form vesicles in aqueous medium. The experimental results based on the control compound and all-atom molecular dynamics (MD) simulations support the mechanism of association through intermolecular π–π interactions between the indole rings of tryptophan residues. These peptide vesicles showed a DOX loading capacity of ∼16% (w/w) and redox-triggered controlled release of the packaged drug. The drug-loaded vesicles were able to penetrate into MDA-MB-231 and HeLa cells, and release payload, suggesting their putative use as chemotherapeutic delivery vehicles. These natural peptide-based carriers disassemble inside cells due to the high cytosolic GSH concentration, and the resultant Cys-Trp dipeptide is degradable. The minimalistic peptide design presented here, coupled with the propensity to form vesicles that can encapsulate the chemotherapeutic drug, opens up unlimited potential for engineering targeted sustained-release drug delivery vehicles.

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