Structural impact of thioamide incorporation into a β-hairpin

Fiore, Kristen E.; Patist, Martijn J.; Giannakoulias, Sam; Huang, Cheng-Hsin; Verma, Hitesh; Khatri, Bhavesh; Cheng, Richard P.; Chatterjee, Jayanta; Petersson, E. James

doi:10.1039/d1cb00229e

Cited by 6 publications

(5 citation statements)

References 81 publications

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“…In a HNCO experiment starting from the amide groups of Lys24 or Ala32, we found values around 184 ppm for the C=O carbon atoms of both modified Cys residues (Fig. 3F), far from 175-ppm and 200-ppm values expected for such atoms in random-coil and thio-amide peptides, respectively (30,33). By increasing the resolution and varying the offset of the decoupling pulse during the C=O evolution period, we determined a 90-Hz coupling constant of both carbonyls with carbon atoms whose chemical shift is ~120 ppm, consistent with their absence in the HNCACB experiment (Fig.…”

Section: Ptm Identification By Nmrmentioning

confidence: 73%

A widespread family of ribosomal peptide metallophores involved in bacterial adaptation to metal stress

Leprevost,

Jünger,

Lippens

et al. 2024

Preprint

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Ribosomally synthesized, post-translationally modified peptides (RiPPs) are increasingly known to play prominent roles in bacterial adaptation. Herein, we identified and characterized a family of RiPP metallophores with rare 5-thiooxazole motifs, whose production is induced by transition metal stress in a number of pathogenic and environmental bacteria. Using Caulobacter vibrioides as a model, we demonstrated that the so-called bufferins confer protection to the bacteria from copper by complexing with the metal. Bufferin biosynthesis requires a multinuclear non-heme iron-dependent oxidase (MNIO, DUF692 family) and its partner protein to install thiooxazoles on Cys residues. By contrast, a hallmark feature of bufferin precursors, the N-terminal signal peptide sequence, is not essential for this transformation. Bufferin-like gene clusters are widespread in Eubacteria, including several pathogens, and the C. vibrioides epitomize the largest two families of RiPPs involving MNIO enzymes. Our study unveils a widespread but overlooked bacterial strategy mediated by a new type of RiPPs to cope with copper stress encountered in the environment and in the phagosomes of predatory protists or mammalian hosts.

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Section: Ptm Identification By Nmrmentioning

confidence: 73%

A widespread family of ribosomal peptide metallophores involved in bacterial adaptation to metal stress

Leprevost,

Jünger,

Lippens

et al. 2024

Preprint

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“…In pharmaceuticals, the presence of the thioamide group can improve biological activities, pharmacokinetic properties, selectivity, elimination of toxicity, and chemical stability (Kumari et al, 2020). That may be related to the effect of hydrogen bond strength and structural effects of modifications to thioamide backbones (Fiore et al, 2022; Lampkin & VanVeller, 2021). Based on the above, our work extended to synthesized quinoxaline sulfonohydrazide derivatives 9 – 11 containing thioamide group from reaction of quinoxaline sulfonyl chloride (QSC) 2 with hydrazine‐1‐carbothioamide derivatives, such as thiosemicarbazide, N ‐methyl thiosemicarbazide, and N ‐allyl thiosemicarbazide.…”

Section: Resultsmentioning

confidence: 99%

Explore new quinoxaline pharmacophore tethered sulfonamide fragments as in vitro α‐glucosidase, α‐amylase, and acetylcholinesterase inhibitors with ADMET and molecular modeling simulation

Ragab,

Salem,

Ammar

et al. 2024

Drug Development Research

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A new series of quinoxaline‐sulfonamide derivatives 3–12 were synthesized using fragment‐based drug design by reaction of quinoxaline sulfonyl chloride (QSC) with different amines and hydrazines. The quinoxaline‐sulfonamide derivatives were evaluated for antidiabetic and anti‐Alzheimer's potential against α‐glucosidase, α‐amylase, and acetylcholinesterase enzymes. These derivatives showed good to moderate potency against α‐amylase and α‐glucosidase with inhibitory percentages between 24.34 ± 0.01%–63.09 ± 0.02% and 28.95 ± 0.04%–75.36 ± 0.01%, respectively. Surprisingly, bis‐sulfonamide quinoxaline derivative 4 revealed the most potent activity with inhibitory percentages of 75.36 ± 0.01% and 63.09 ± 0.02% against α‐glucosidase and α‐amylase compared to acarbose (IP = 57.79 ± 0.01% and 67.33 ± 0.01%), respectively. Moreover, the quinoxaline derivative 3 exhibited potency as α‐glucosidase and α‐amylase inhibitory with a minute decline from compound 4 and acarbose with inhibitory percentages of 44.93 ± 0.01% and 38.95 ± 0.01%. Additionally, in vitro acetylcholinesterase inhibitory activity for designed derivatives exhibited weak to moderate activity. Still, sulfonamide‐quinoxaline derivative 3 emerged as the most active member with inhibitory percentage of 41.92 ± 0.02% compared with donepezil (IP = 67.27 ± 0.60%). The DFT calculations, docking simulation, target prediction, and ADMET analysis were performed and discussed in detail.

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“…A priori prediction of optimal amide-to-thioamide replacement sites does not seem to be possible at this point, but preparation and evaluation of a small set of derivatives of a given antigen, comprising 10–15 analogues, should allow the identification of thio-antigens with promising properties. Synthesis of such thioamide-substituted peptides is straightforward. ,,,− ,− …”

Section: Discussionmentioning

confidence: 99%

Thioamide Analogues of MHC I Antigen Peptides

Gibadullin,

Morris,

Niu

et al. 2023

J. Am. Chem. Soc.

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Short, synthetic peptides that are displayed by major histocompatibility complex I (MHC I) can stimulate CD8 T cells in vivo to destroy virus-infected or cancer cells. The development of such peptides as vaccines that provide protective immunity, however, is limited by rapid proteolytic degradation. Introduction of unnatural amino acid residues can suppress MHC I antigen proteolysis, but the modified peptides typically display lower affinity for MHC I and/or diminished ability to activate CD8 T cells relative to native antigen. Here, we report a new strategy for modifying MHC I antigens to enhance resistance to proteolysis while preserving MHC I affinity and T cell activation properties. This approach, replacing backbone amide groups with thioamides, was evaluated in two well-characterized antigens presented by HLA-A2, a common human MHC I. For each antigen, singly modified thioamide analogues retained affinity for HLA-A2 and activated T cells specific for the native antigen, as measured via interferon-γ secretion. In each system, we identified a highly potent triply substituted thioamide antigen ("thio-antigen") that displayed substantial resistance to proteolytic cleavage. Collectively, our results suggest that thio-antigens may represent a general and readily accessible source of potent vaccine candidates that resist degradation.

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Structural impact of thioamide incorporation into a β-hairpin

Abstract: NMR studies of macrocyclic β-hairpin model systems demonstrate that thioamides can be tolerated at both hydrogen bond donor and hydrogen bond acceptor positions.

Cited by 6 publications

References 81 publications

A widespread family of ribosomal peptide metallophores involved in bacterial adaptation to metal stress

A widespread family of ribosomal peptide metallophores involved in bacterial adaptation to metal stress

Explore new quinoxaline pharmacophore tethered sulfonamide fragments as in vitro α‐glucosidase, α‐amylase, and acetylcholinesterase inhibitors with ADMET and molecular modeling simulation

Thioamide Analogues of MHC I Antigen Peptides

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