Disulfide-rich macrocyclic peptides as templates in drug design

Northfield, Susan E.; Wang, Conan K.; Schroeder, Christina I.; Durek, Thomas; Kan, Meng‐Wei; Swedberg, Joakim E.; Craik, David J.

doi:10.1016/j.ejmech.2014.03.011

Cited by 127 publications

(112 citation statements)

References 125 publications

Supporting

Mentioning

110

Contrasting

Unclassified

Order By: Relevance

“…They show beneficial biological properties, such as anticancer and anti-HIV activity, making them attractive candidates for pharmaceutical applications. Moreover, other bioactive sequences can be stabilized by grafting into cyclotide frameworks (Northfield et al, 2014).…”

Section: Structural Aspects Of Bioactive Sequencesmentioning

confidence: 99%

Structural aspects of legume proteins and nutraceutical properties

Carbonaro

Maselli

Nucara

2015

Food Research International

175

120

View full text Add to dashboard Cite

Section: Structural Aspects Of Bioactive Sequencesmentioning

confidence: 99%

Structural aspects of legume proteins and nutraceutical properties

Carbonaro

Maselli

Nucara

2015

Food Research International

175

120

View full text Add to dashboard Cite

“…cyclic peptide | permeability | N-methylation P eptides are potentially valuable compounds for drug development, offering many advantages over other molecular classes (1)(2)(3)(4). Specifically, their ability to mimic endogenous bioactive molecules allows them to bind potently and selectively to "difficult" drug targets, including protein-protein interactions that are too challenging for small-molecule therapeutics.…”

mentioning

confidence: 99%

Rational design and synthesis of an orally bioavailable peptide guided by NMR amide temperature coefficients

Wang

Northfield

Colless

et al. 2014

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

Self Cite

143

153

View full text Add to dashboard Cite

Enhancing the oral bioavailability of peptide drug leads is a major challenge in drug design. As such, methods to address this challenge are highly sought after by the pharmaceutical industry. Here, we propose a strategy to identify appropriate amides for N-methylation using temperature coefficients measured by NMR to identify exposed amides in cyclic peptides. N-methylation effectively caps these amides, modifying the overall solvation properties of the peptides and making them more membrane permeable. The approach for identifying sites for N-methylation is a rapid alternative to the elucidation of 3D structures of peptide drug leads, which has been a commonly used structure-guided approach in the past. Five leucine-rich peptide scaffolds are reported with selectively designed N-methylated derivatives. In vitro membrane permeability was assessed by parallel artificial membrane permeability assay and Caco-2 assay. The most promising N-methylated peptide was then tested in vivo. Here we report a novel peptide (15), which displayed an oral bioavailability of 33% in a rat model, thus validating the design approach. We show that this approach can also be used to explain the notable increase in oral bioavailability of a somatostatin analog.cyclic peptide | permeability | N-methylation P eptides are potentially valuable compounds for drug development, offering many advantages over other molecular classes (1-4). Specifically, their ability to mimic endogenous bioactive molecules allows them to bind potently and selectively to "difficult" drug targets, including protein-protein interactions that are too challenging for small-molecule therapeutics. However, the widespread use of peptides in the clinic has been slow in coming, in large part because of their generally low stability in vivo, high clearance, and poor oral bioavailability.The low oral bioavailability of peptides is attributed to a disparity between their physicochemical properties and those traditionally expected for "drug-likeness" (5, 6), leading to a perception that peptides are good drug leads but poor drugs. However, this perception is being challenged by a growing number of peptides that seem to be stable (7) and well absorbed within the gastrointestinal tract (8) and examples in which cyclic peptides have shown orally delivered bioactivity in animal disease models, including inflammatory pain (9) and neuropathic pain (10), prompting us to devise new rules for predicting pharmacokinetic properties of this compound class. Arguably the most famous example of a peptide with poor drug-likeness but reasonable oral bioavailability is cyclosporin A, widely used as the immunosuppressant drug cyclosporine (11). Two structural features of cyclosporin A in particular are thought to contribute to its oral bioavailability, namely its macrocyclic architecture and backbone N-methylation.Cyclization imparts increased rigidity to a parent peptide, which not only improves its stability against proteolytic degradation but also directs it into specific conformations that m...

show abstract

“…It had been proposed that the role of disulfide bonds in defensins was to bolster antimicrobial activity by allowing the peptides to remain stable in a diverse range of environments (Northfield et al, 2014). During the courses of the two simulations, the distance of sulfur atoms of Cys23 and Cys41 sometimes became larger, while the atoms were still linked for most of time.…”

Section: Resultsmentioning

confidence: 99%

Insight into the impact of environments on structure of chimera C3 of human β-defensins 2 and 3 from molecular dynamics simulations

Zhao

et al. 2014

Journal of Biomolecular Structure and Dynamics

View full text Add to dashboard Cite

C3 is a chimera from human β-defensins 2 and 3 and possesses higher antimicrobial activity compared with its parental molecules, so it is an attractive candidate for clinical application of antimicrobial peptides. In continuation with the previous studies, molecular dynamics (MD) simulations were carried out for further investigating the effect of ambient environments (temperature and bacterial membrane) on C3 dynamics. Our results reveal that C3 has higher flexibility, larger intensity of motion, and more relevant secondary structural changes at 363 K to adapt the high temperature and maintain its antimicrobial activity, comparison with it at 293 K; when C3 molecule associates with the bacterial membrane, it slightly fluctuates and undergoes local conformational changes; in summary, C3 molecule demonstrates stable conformations under these environments. Furthermore, MD results analysis show that the hydrophobic contacts, the hydrogen bonds, and disulfide bonds in the peptide are responsible for maintaining its stable conformation. In addition, our simulation shows that C3 peptides can make anionic lipids clustered in the bacterial membrane; it means that positive charges and pronounced regional cationic charge density of C3 are most key factors for its antimicrobial activity.

show abstract

Disulfide-rich macrocyclic peptides as templates in drug design

Cited by 127 publications

References 125 publications

Structural aspects of legume proteins and nutraceutical properties

Structural aspects of legume proteins and nutraceutical properties

Rational design and synthesis of an orally bioavailable peptide guided by NMR amide temperature coefficients

Insight into the impact of environments on structure of chimera C3 of human β-defensins 2 and 3 from molecular dynamics simulations

Contact Info

Product

Resources

About