Immunosilencing peptides by stereochemical inversion and sequence reversal: retro-D-peptides

Arranz‐Gibert, Pol; Ciudad, Sonia; Seco, Jesús; García, Jesús; Giralt, Ernest; Teixidó, Meritxell

doi:10.1038/s41598-018-24517-6

Cited by 32 publications

(25 citation statements)

References 47 publications

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“…In this study, the scope of the N -(methoxy)oxazolidine ligation was expanded by the synthesis of a more diverse set of conjugates. U NOMe -extended ONs, consisting of three therapeutically relevant ONs, ISE-AR-V7 [ 38 ], Nusinersen [ 39 ], IONIS-DGAT2 RX [ 40 , 41 ], and one DNA-aptamer, TfRA3 [ 42 ], were synthesized and conjugated to four different β-Ala-H-containing biomolecules: SpyTag [ 43 ], D-retro inverso THR [ 44 , 45 , 46 ], an antisense PNA [ 47 ], and a trivalent N -acetyl galactosamine (GalNAc) cluster (cf. further description of these biomolecules below).…”

Section: Introductionmentioning

confidence: 99%

Expanding the Scope of the Cleavable N-(Methoxy)oxazolidine Linker for the Synthesis of Oligonucleotide Conjugates

et al. 2021

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Oligonucleotides modified by a 2′-deoxy-2′-(N-methoxyamino) ribonucleotide react readily with aldehydes in slightly acidic conditions to yield the corresponding N-(methoxy)oxazolidine-linked oligonucleotide-conjugates. The reaction is reversible and dynamic in slightly acidic conditions, while the products are virtually stable above pH 7, where the reaction is in a ‘‘switched off-state’’. Small molecular examinations have demonstrated that aldehyde constituents affect the cleavage rate of the N-(methoxy)oxazolidine-linkage. This can be utilized to adjust the stability of this pH-responsive cleavable linker for drug delivery applications. In the present study, Fmoc-β-Ala-H was immobilized to a serine-modified ChemMatrix resin and used for the automated assembly of two peptidealdehydes and one aldehyde-modified peptide nucleic acid (PNA). In addition, a triantennary N-acetyl-d-galactosamine-cluster with a β-Ala-H unit has been synthesized. These aldehydes were conjugated via N-(methoxy)oxazolidine-linkage to therapeutically relevant oligonucleotide phosphorothioates and one DNA-aptamer in 19–47% isolated yields. The cleavage rates of the conjugates were studied in slightly acidic conditions. In addition to the diverse set of conjugates synthesized, these experiments and a comparison to published data demonstrate that the simple conversion of Gly-H to β-Ala-H residue resulted in a faster cleavage of the N-(methoxy)oxazolidine-linker at pH 5, being comparable (T0.5 ca 7 h) to hydrazone-based structures.

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Section: Introductionmentioning

confidence: 99%

Expanding the Scope of the Cleavable N-(Methoxy)oxazolidine Linker for the Synthesis of Oligonucleotide Conjugates

et al. 2021

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“…1 ). Since the arrangement of d -amino acids in a reverse sequence to the l -parent peptide can lead to a conformation that achieves a good mimicry with the l -peptide 8 , the retro-enantio version of the E1P47 (RE-E1P4) peptide was synthesized (Fig. 1 B).…”

Section: Resultsmentioning

confidence: 99%

“…In addition, it has been recently reported that d -peptides derived from a parent sequence not related to any existing protein silence the immune system and avoid specific humoral responses. Thus retro-D peptides, which display a similar topological arrangement as their parent peptides, offer the advantage of overcoming immunological problems when they are used as therapeutic agents 8 . Despite these advantages, a limited number of studies have addressed the therapeutic usefulness of d -peptide structures as HIV-1 fusion inhibitors 9 .…”

Section: Introductionmentioning

confidence: 99%

Importance of structure-based studies for the design of a novel HIV-1 inhibitor peptide

Gómara

Pérez

Gómez-Gutiérrez

et al. 2020

Sci Rep

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Based on the structure of an HIV-1 entry inhibitor peptide two stapled-and a retro-enantio peptides have been designed to provide novel prevention interventions against HiV transmission. the three peptides show greater inhibitory potencies in cellular and mucosal tissue pre-clinical models than the parent sequence and the retro-enantio shows a strengthened proteolytic stability. Since HIV-1 fusion inhibitor peptides need to be embedded in the membrane to properly interact with their viral target, the structural features were determined by NMR spectroscopy in micelles and solved by using restrained molecular dynamics calculations. Both parent and retro-enantio peptides demonstrate a topology compatible with a shared helix-turn-helix conformation and assemble similarly in the membrane maintaining the active conformation needed for its interaction with the viral target site. This study represents a straightforward approach to design new targeted peptides as HIV-1 fusion inhibitors and lead us to define a retro-enantio peptide as a good candidate for pre-exposure prophylaxis against HIV-1. The therapeutic utility of synthetic peptides as Human Immunodeficiency Virus (HIV) fusion inhibitors is largely limited due to their natural proteogenic structure, which is easily recognized and degraded by proteolytic enzymes. This limitation has hampered the clinical use of T20, a 36-mer peptide that binds to the HIV-1 gp41, and requires high dosing and repeated injections due to its lack of oral bioavailability 1,2. Among the different strategies studied to improve the pharmacokinetic behaviour of peptides composed of natural amino acids, the synthetic d-peptides have demonstrated a higher enzymatic stability, an increased serum half-life and the possibility to be absorbed systemically when taken orally 3,4. d-amino acids decrease the substrate recognition and binding affinity of proteolytic enzymes and confer enzymatic stability to d-peptides 5-7. In addition, it has been recently reported that d-peptides derived from a parent sequence not related to any existing protein silence the immune system and avoid specific humoral responses. Thus retro-D peptides, which display a similar topological arrangement as their parent peptides, offer the advantage of overcoming immunological problems when they are used as therapeutic agents 8. Despite these advantages, a limited number of studies have addressed the therapeutic usefulness of d-peptide structures as HIV-1 fusion inhibitors 9. However, it is worth mentioning 10,11 the cyclic and trimeric d-peptide inhibitors that target the gp41 coiled-coil pocket as well as their subsequent modifications to increase the pharmacokinetics profiles and anti-viral activity 12,13. Alternatively to the use of non-natural amino acids, the introduction of conformational restrictions in linear peptide sequences has been widely used as an strategy to overcome peptide flexibility improving their biological potency 14. Particularly, it has been described the stapling technique which consists on the covalen...

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“…This “immunosilencing” behavior was reversed when the peptide was conjugated to Keyhole limpet hemocyanin. The complex elicited IR in rabbit, suggesting that retro-D class of peptides can also be used as vaccines (Arranz-Gibert et al 2018 ). Substitution of the residues that interact with HLA or T-cell receptors with NPAAs may reduce the risk of immunogenicity (Meister et al 2019 ).…”

Section: Npaas and Oral Bioavailabilitymentioning

confidence: 99%

Impact of non-proteinogenic amino acids in the discovery and development of peptide therapeutics

et al. 2020

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With the development of modern chemistry and biology, non-proteinogenic amino acids (NPAAs) have become a powerful tool for developing peptide-based drug candidates. Drug-like properties of peptidic medicines, due to the smaller size and simpler structure compared to large proteins, can be changed fundamentally by introducing NPAAs in its sequence. While peptides composed of natural amino acids can be used as drug candidates, the majority have shown to be less stable in biological conditions. The impact of NPAA incorporation can be extremely beneficial in improving the stability, potency, permeability, and bioavailability of peptide-based therapies. Conversely, undesired effects such as toxicity or immunogenicity should also be considered. The impact of NPAAs in the development of peptide-based therapeutics is reviewed in this article. Further, numerous examples of peptides containing NPAAs are presented to highlight the ongoing development in peptide-based therapeutics.

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Immunosilencing peptides by stereochemical inversion and sequence reversal: retro-D-peptides

Cited by 32 publications

References 47 publications

Expanding the Scope of the Cleavable N-(Methoxy)oxazolidine Linker for the Synthesis of Oligonucleotide Conjugates

Expanding the Scope of the Cleavable N-(Methoxy)oxazolidine Linker for the Synthesis of Oligonucleotide Conjugates

Importance of structure-based studies for the design of a novel HIV-1 inhibitor peptide

Impact of non-proteinogenic amino acids in the discovery and development of peptide therapeutics

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