N-sulfonyl peptide-hybrids as a new class of dengue virus protease inhibitors

Behrouz, Somayeh; Kühl, Nikos; Klein, Christian D.

doi:10.1016/j.ejmech.2023.115227

Cited by 8 publications

(4 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This trend was also noted in cell-based assays where peptides capped with hydrophobic rhodanines demonstrated greater anti-viral activity. Recently, N-sulfonyl-capped peptides have emerged as novel anti-DENV PDCs, with the most potent derivatives achieving double-digit nanomolar inhibition constants . Remarkably, these compounds have demonstrated high DENV protease selectivity, limited cytotoxicity and significant metabolic stability, indicating that they may represent strong candidates for clinical applications.…”

Section: Anti-viral Peptide–drug Conjugatesmentioning

confidence: 99%

Peptide–Drug Conjugates: An Emerging Direction for the Next Generation of Peptide Therapeutics

Dean,

Jelú-Reyes,

Allen

et al. 2024

J. Med. Chem.

View full text Add to dashboard Cite

Building on recent advances in peptide science, medicinal chemists have developed a hybrid class of bioconjugates, called peptide−drug conjugates, that demonstrate improved efficacy compared to peptides and small molecules independently. In this Perspective, we discuss how the conjugation of synergistic peptides and small molecules can be used to overcome complex disease states and resistance mechanisms that have eluded contemporary therapies because of their multi-component activity. We highlight how peptide−drug conjugates display a multi-factor therapeutic mechanism similar to that of antibody−drug conjugates but also demonstrate improved therapeutic properties such as less-severe off-target effects and conjugation strategies with greater site-specificity. The many considerations that go into peptide−drug conjugate design and optimization, such as peptide/smallmolecule pairing and chemo-selective chemistries, are discussed. We also examine several peptide−drug conjugate series that demonstrate notable activity toward complex disease states such as neurodegenerative disorders and inflammation, as well as viral and bacterial targets with established resistance mechanisms. ■ SIGNIFICANCE• Juxtaposition of peptide−drug conjugates and antibody−drug conjugates with a focus on challenges that can be overcome with peptide−drug conjugate strategies. • Considerations for the design and optimization of peptide−drug conjugates. • Analysis of several peptide−drug conjugate series that demonstrate effectiveness toward drug-resistant infections and complex disease states.

show abstract

Section: Anti-viral Peptide–drug Conjugatesmentioning

confidence: 99%

Peptide–Drug Conjugates: An Emerging Direction for the Next Generation of Peptide Therapeutics

Dean,

Jelú-Reyes,

Allen

et al. 2024

J. Med. Chem.

View full text Add to dashboard Cite

show abstract

“…Indeed, the authors have observed that replacement of the amide group with a sulfonamide at the N-terminal of DENV protease inhibitors has shown an improved metabolic stability against rat liver microsomes, although some loss in activity was observed. Nevertheless, it was observed that the presence of the sulfonamide groups has also improved stability and off-target selectivity against pancreatic serine proteases, trypsin and α-chymotrypsin, and thrombin [ 50 ].…”

Section: Inhibition Of Viral Proteases By Targeting the Active Sitementioning

confidence: 99%

“…Indeed, the authors have observed that re- The stability of the amide bond surrogates is an important factor when developing peptidomimetic inhibitors, since it can have a direct impact not only on inhibitory activity, for example as seen for 15, but more importantly on the bioavailability of such compounds, by preventing degradation by host peptidases [49]. In a more recent study, Behrouz et al designed potent peptidomimetic inhibitors containing a sulfonyl moiety as N-terminal cap [50]. Sulfonamides are important structural motifs that can be regarded as surrogates that mimic peptide bonds while maintaining an increased bioavailability and stability towards proteolytic degradation [51].…”

Section: Peptide-based Moleculesmentioning

confidence: 99%

Recent Advances on Targeting Proteases for Antiviral Development

Borges,

Ferreira,

Silva

2024

Viruses

View full text Add to dashboard Cite

Viral proteases are an important target for drug development, since they can modulate vital pathways in viral replication, maturation, assembly and cell entry. With the (re)appearance of several new viruses responsible for causing diseases in humans, like the West Nile virus (WNV) and the recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), understanding the mechanisms behind blocking viral protease’s function is pivotal for the development of new antiviral drugs and therapeutical strategies. Apart from directly inhibiting the target protease, usually by targeting its active site, several new pathways have been explored to impair its activity, such as inducing protein aggregation, targeting allosteric sites or by inducing protein degradation by cellular proteasomes, which can be extremely valuable when considering the emerging drug-resistant strains. In this review, we aim to discuss the recent advances on a broad range of viral proteases inhibitors, therapies and molecular approaches for protein inactivation or degradation, giving an insight on different possible strategies against this important class of antiviral target.

show abstract

“…The capping motif phenomenon in linear peptides also encompasses terminal modifications ( Table 1 ). These modifications can prevent chain degradation by reducing the vulnerability of peptide bonds to proteolytic cleavage ( Behrouz et al, 2023 ; Ding et al, 2023 ). Furthermore, specific modifications at the ends of sequences employ unconventional conformational motifs, forming intramolecular H-bond pairs to enhance both the structural characteristics and activity of AMPs ( Aurora and Rose, 1998 ).…”

Section: Capping Motif Effects Due To Unusual Groups For Amp Optimiza...mentioning

confidence: 99%

Capping motifs in antimicrobial peptides and their relevance for improved biological activities

Brango-Vanegas,

Leite,

Macedo

et al. 2024

Front. Chem.

View full text Add to dashboard Cite

N-capping (N-cap) and C-capping (C-cap) in biologically active peptides, including specific amino acids or unconventional group motifs, have been shown to modulate activity against pharmacological targets by interfering with the peptide’s secondary structure, thus generating unusual scaffolds. The insertion of capping motifs in linear peptides has been shown to prevent peptide degradation by reducing its susceptibility to proteolytic cleavage, and the replacement of some functional groups by unusual groups in N- or C-capping regions in linear peptides has led to optimized peptide variants with improved secondary structure and enhanced activity. Furthermore, some essential amino acid residues that, when placed in antimicrobial peptide (AMP) capping regions, are capable of complexing metals such as Cu2+, Ni2+, and Zn2+, give rise to the family known as metallo-AMPs, which are capable of boosting antimicrobial efficacy, as well as other activities. Therefore, this review presents and discusses the different strategies for creating N- and C-cap motifs in AMPs, aiming at fine-tuning this class of antimicrobials.

show abstract

N-sulfonyl peptide-hybrids as a new class of dengue virus protease inhibitors

Cited by 8 publications

References 50 publications

Peptide–Drug Conjugates: An Emerging Direction for the Next Generation of Peptide Therapeutics

Peptide–Drug Conjugates: An Emerging Direction for the Next Generation of Peptide Therapeutics

Recent Advances on Targeting Proteases for Antiviral Development

Capping motifs in antimicrobial peptides and their relevance for improved biological activities

Contact Info

Product

Resources

About