Thia-Michael addition: the route to promising opportunities for fast and cysteine-specific modification

Brimble, Margaret A.; Ahangarpour, Marzieh; Kavianinia, Iman

doi:10.1039/d2ob02262a

Cited by 19 publications

(7 citation statements)

References 90 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…116 Another approach for selective cysteine modication in peptides and proteins utilises the thia-Michael addition. 117 Zhou & co-workers introduced 5-methylene pyrrolone and its halo-derivatives as Michael acceptors which form cysteine conjugates at physiological pH (Scheme 4C). This bioconjugation strategy has been used for protein modication and disulde replacement in the hormone somatostatin (Scheme 4C).…”

Section: Dithiol Bisalkylationmentioning

confidence: 99%

Biocompatible strategies for peptide macrocyclisation

He,

Ghosh,

Nitsche

2024

Chem. Sci.

View full text Add to dashboard Cite

show abstract

Section: Dithiol Bisalkylationmentioning

confidence: 99%

Biocompatible strategies for peptide macrocyclisation

He,

Ghosh,

Nitsche

2024

Chem. Sci.

View full text Add to dashboard Cite

show abstract

“…Originally developed as kinase inhibitors, covalently binding inhibitors carry a specific functional group, so called warheads, e.g., an α-β-unsaturated carbonyl moiety. This electrophilic functionality can interact with an accessible nucleophilic residue at its biological target, normally a cysteine residue (Michael addition reaction) [ 107 , 108 , 109 , 110 ]. While the covalent target linkage of warheads is thereby achieved through the Michael addition reaction, binding specificity is mediated by the drug scaffold.…”

Section: The Multifaceted Aspects Of Nec-directed Antiviral Drug Targ...mentioning

confidence: 99%

“…Sci. 2024, 25, x FOR PEER REVIEW 14 of 26 philic residue at its biological target, normally a cysteine residue (Michael addition reaction) [107][108][109][110]. While the covalent target linkage of warheads is thereby achieved through the Michael addition reaction, binding specificity is mediated by the drug scaffold.…”

Section: Covalently Target-binding Warheads Can Possess An Nec-direct...mentioning

confidence: 99%

‘Getting Better’—Is It a Feasible Strategy of Broad Pan-Antiherpesviral Drug Targeting by Using the Nuclear Egress-Directed Mechanism?

Tillmanns,

Kicuntod,

Lösing

et al. 2024

IJMS

View full text Add to dashboard Cite

The herpesviral nuclear egress represents an essential step of viral replication efficiency in host cells, as it defines the nucleocytoplasmic release of viral capsids. Due to the size limitation of the nuclear pores, viral nuclear capsids are unable to traverse the nuclear envelope without a destabilization of this natural host-specific barrier. To this end, herpesviruses evolved the regulatory nuclear egress complex (NEC), composed of a heterodimer unit of two conserved viral NEC proteins (core NEC) and a large-size extension of this complex including various viral and cellular NEC-associated proteins (multicomponent NEC). Notably, the NEC harbors the pronounced ability to oligomerize (core NEC hexamers and lattices), to multimerize into higher-order complexes, and, ultimately, to closely interact with the migrating nuclear capsids. Moreover, most, if not all, of these NEC proteins comprise regulatory modifications by phosphorylation, so that the responsible kinases, and additional enzymatic activities, are part of the multicomponent NEC. This sophisticated basis of NEC-specific structural and functional interactions offers a variety of different modes of antiviral interference by pharmacological or nonconventional inhibitors. Since the multifaceted combination of NEC activities represents a highly conserved key regulatory stage of herpesviral replication, it may provide a unique opportunity towards a broad, pan-antiherpesviral mechanism of drug targeting. This review presents an update on chances, challenges, and current achievements in the development of NEC-directed antiherpesviral strategies.

show abstract

“…Among these methods, diverse chemical strategies and coupling reagents provide rich solutions for accessing cysteine (Cys)‐specific peptides and/or protein modifications due to the inherent strong nucleophilicity, low redox potential, and low abundance of Cys compared to other classic amino acids. [ 3 ] In addition to classic strategies, including nucleophilic substitution (iodoacetamides), [ 4 ] S‐Michael‐type addition (maleimide derivatives), [ 5 ] and disulfide exchange reactions, [ 6 ] there are also some innovative methods reported and applied, such as reactions with activated heteroaromatic compounds, [ 7 ] hypervalent iodine reagents, [ 8 ] cationic activation reagents, [ 9 ] strain‐releasing reagents, [ 10 ] and reactions via photocatalysis [ 11 ] ( Figure 1 A1 ). Despite these advances, there is a continued demand for methods that are simple, efficient, and “cost‐effective” and exhibit high atomic utilization.…”

Section: Introductionmentioning

confidence: 99%

Cysteine‐Specific Multifaceted Bioconjugation of Peptides and Proteins Using 5‐Substituted 1,2,3‐Triazines

Zuo,

Li,

Lai

et al. 2024

Advanced Science

View full text Add to dashboard Cite

Peptide and protein postmodification have gained significant attention due to their extensive impact on biomolecule engineering and drug discovery, of which cysteine‐specific modification strategies are prominent due to their inherent nucleophilicity and low abundance. Herein, the study introduces a novel approach utilizing multifunctional 5‐substituted 1,2,3‐triazine derivatives to achieve multifaceted bioconjugation targeting cysteine‐containing peptides and proteins. On the one hand, this represents an inaugural instance of employing 1,2,3‐triazine in biomolecular‐specific modification within a physiological solution. On the other hand, as a powerful combination of precision modification and biorthogonality, this strategy allows for the one‐pot dual‐orthogonal functionalization of biomolecules utilizing the aldehyde group generated simultaneously. 1,2,3‐Triazine derivatives with diverse functional groups allow conjugation to peptides or proteins, while bi‐triazines enable peptide cyclization and dimerization. The examination of the stability of bi‐triazines revealed their potential for reversible peptide modification. This work establishes a comprehensive platform for identifying cysteine‐selective modifications, providing new avenues for peptide‐based drug development, protein bioconjugation, and chemical biology research.

show abstract

Thia-Michael addition: the route to promising opportunities for fast and cysteine-specific modification

Abstract: Over the last few decades, design and discovery of chemical reactions that enable modification of proteins at pre-determined sites have been the focus of synthetic organic chemists. As an invaluable...

Cited by 19 publications

References 90 publications

Biocompatible strategies for peptide macrocyclisation

Biocompatible strategies for peptide macrocyclisation

‘Getting Better’—Is It a Feasible Strategy of Broad Pan-Antiherpesviral Drug Targeting by Using the Nuclear Egress-Directed Mechanism?

Cysteine‐Specific Multifaceted Bioconjugation of Peptides and Proteins Using 5‐Substituted 1,2,3‐Triazines

Contact Info

Product

Resources

About