Sequential native peptide ligation strategies for total chemical protein synthesis

Raibaut, Laurent; Ollivier, Nathalie; Melnyk, Oleg

doi:10.1039/c2cs35147a

Cited by 202 publications

(109 citation statements)

References 63 publications

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“…Conjugation of peptides, became a popular approach for the synthesis of chemically engineered biomolecules for various biological applications. 21 Peptides ligation is a smart solution to overcome the obstacles in obtaining large homogeneous peptides with more than 50 amino acids by using solid phase peptide synthesis (SPPS). 22 Many peptide ligation techniques were revealed for the conjugation of two peptides via the binding of amino (N) terminal of one of the peptides to the carboxy (C) terminal of the other one.…”

Section: Synthesis and Characterization Of Polymer-peptide Conjugatesmentioning

confidence: 99%

Multiantigenic peptide–polymer conjugates as therapeutic vaccines against cervical cancer

Hussein

Liu

Jia

et al. 2016

Bioorganic & Medicinal Chemistry

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Immunotherapy is one of the most promising strategies for the treatment of cancer. Human papillomavirus (HPV) is responsible for virtually all cases of cervical cancer. The main purpose of a therapeutic HPV vaccine is to stimulate CD8 + cytotoxic T lymphocytes (CTLs) that can eradicate HPV infected cells. HPV oncoproteins E6 and E7 are continuously expressed and are essential for maintaining the growth of HPV-associated tumor cells. We designed polymer-based multi-antigenic formulations/constructs that were comprised of the E6 and E7 peptide epitopes.We developed an N-terminus-based epitope conjugation to conjugate two unprotected peptides to poly tert-butyl acrylate. This method allowed for the incorporation of the two antigens into a polymeric dendrimer in a strictly equimolar ratio. The most effective formulations eliminated tumors in up to 50% of treated mice. Tumor recurrence was not observed up to 3 months post initial challenge.

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Section: Synthesis and Characterization Of Polymer-peptide Conjugatesmentioning

confidence: 99%

Multiantigenic peptide–polymer conjugates as therapeutic vaccines against cervical cancer

Hussein

Liu

Jia

et al. 2016

Bioorganic & Medicinal Chemistry

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“…Because the composition of phospholipids controls the physical properties of the resulting membranes, synthetic phospholipid remodeling could be used to gain control over the function and form of artificial membranes, for instance by enabling dynamic changes in vesicle morphology. Here, we demonstrate efficient de novo generation and remodeling of phospholipid vesicles at neutral pH through application of the native chemical ligation (NCL) (13)(14)(15)(16)(17)(18) and reversible native chemical ligation (RNCL) (19) (Fig. 1 B and C and SI Appendix, Figs.…”

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confidence: 99%

Nonenzymatic biomimetic remodeling of phospholipids in synthetic liposomes

Brea

Rudd

Devaraj

2016

Proc. Natl. Acad. Sci. U.S.A.

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Cell membranes have a vast repertoire of phospholipid species whose structures can be dynamically modified by enzymatic remodeling of acyl chains and polar head groups. Lipid remodeling plays important roles in membrane biology and dysregulation can lead to disease. Although there have been tremendous advances in creating artificial membranes to model the properties of native membranes, a major obstacle has been developing straightforward methods to mimic lipid membrane remodeling. Stable liposomes are typically kinetically trapped and are not prone to exchanging diacylphospholipids. Here, we show that reversible chemoselective reactions can be harnessed to achieve nonenzymatic spontaneous remodeling of phospholipids in synthetic membranes. Our approach relies on transthioesterification/ acyl shift reactions that occur spontaneously and reversibly between tertiary amides and thioesters. We demonstrate exchange and remodeling of both lipid acyl chains and head groups. Using our synthetic model system we demonstrate the ability of spontaneous phospholipid remodeling to trigger changes in vesicle spatial organization, composition, and morphology as well as recruit proteins that can affect vesicle curvature. Membranes capable of chemically exchanging lipid fragments could be used to help further understand the specific roles of lipid structure remodeling in biological membranes.L iving organisms carry out the de novo synthesis of phospholipid membranes, in part, by using membrane-bound acyltransferases and reactive thioester precursors ( Fig. 1A) (1). Subsequently, de novo synthesized phospholipid membranes can be remodeled by acyltransferases and transacylases in the presence of different lysolipid, phospholipid, and fatty acid precursors ( Fig. 1A) (2). Such natural mechanisms allow cells to fine-tune properties of biological membranes by changing the composition and organization of their constituent lipids and proteins (3). Membrane remodeling is an essential component of numerous cellular functions including the formation of organelles (4), division (5), trafficking (6), and signaling (7). Many experimental and theoretical studies have examined membrane remodeling due to enzymatically driven changes in lipid composition (8). For instance, the disruption of the transacylase activity of the enzyme tafazzin leads to alterations in the mitochondrial lipid cardiolipin and the disease known as Barth's syndrome (9).Model membranes composed of well-defined synthetic lipids are useful tools for studying questions related to membrane biology (10, 11). The importance of lipid remodeling in biology underscores the need for straightforward methods to remodel lipid composition in artificial model membranes. Unfortunately, nonenzymatic methods to exchange lysolipid fragments in synthetic vesicles have previously not been feasible. This is likely due to the high kinetic stability of phospholipid membranes, which do not readily exchange diacylphospholipid species between membranes (12). Because the composition of phospholipids c...

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“…[6] It is envisaged that one-pot four-segment ligation will also be an important method for protein chemical synthesis. [7,8] Indeed, in the development of labeled chemokines we encountered the need to establish a one-pot four-segment method to prepare these proteins containing multiple cysteine (Cys) residues.…”

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confidence: 99%

An Efficient One‐Pot Four‐Segment Condensation Method for Protein Chemical Synthesis

et al. 2015

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Successive peptide ligation using a one-pot method can improve the efficiency of protein chemical synthesis. Although one-pot three-segment ligation has enjoyed widespread application, a robust method for one-pot four-segment ligation had to date remained undeveloped. Herein we report a new one-pot multisegment peptide ligation method that can be used to condense up to four segments with operational simplicity and high efficiency. Its practicality is demonstrated by the one-pot four-segment synthesis of a plant protein, crambin, and a human chemokine, hCCL21.

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Sequential native peptide ligation strategies for total chemical protein synthesis

Cited by 202 publications

References 63 publications

Multiantigenic peptide–polymer conjugates as therapeutic vaccines against cervical cancer

Multiantigenic peptide–polymer conjugates as therapeutic vaccines against cervical cancer

Nonenzymatic biomimetic remodeling of phospholipids in synthetic liposomes

An Efficient One‐Pot Four‐Segment Condensation Method for Protein Chemical Synthesis

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