4 research outputs found
A Phage-Compatible Strategy to Access Macrocyclic Peptides Featuring Asymmetric Molecular Scaffolds as Cyclization Units
No full textThe cyclization of peptides appended onto proteins or whole bacteriophages is typically
achieved via disulfide formation, the use of symmetric crosslinkers or the incorporation of noncanonical amino acids. Unfortunately, neither of these strategies is amenable toward generating
libraries for the selection of macrocyclic peptides (MPs) akin to those found in nature, which
often feature asymmetric molecular scaffolds as cyclization units that improve binding to their
targets. To meet this challenge, we present an efficient two-step strategy to access MPs via the
programmed modification of a unique cysteine residue and an N-terminal amine. We
demonstrate that this approach yields MPs featuring asymmetric cyclization units from both
synthetic peptides and when linear precursors are appended onto a phage-coat protein. Given
that the employed conditions are compatible with phage display protocols, our work paves the
way for the selection of natural-product-like MPs from randomized peptide sequences by phage
display
A Strategy to Select Macrocyclic Peptides Featuring Asymmetric Molecular Scaffolds as Cyclization Units by Phage Display
No full textMacrocyclic
peptides
(MPs) have positioned themselves as a privileged
class of compounds for the discovery of therapeutics and development
of chemical probes. Aided by the development of powerful selection
strategies, high-affinity binders against biomolecular targets can
readily be elicited from massive, genetically encoded libraries by
affinity selection. For example, in phage display, MPs are accessed
on the surface of whole bacteriophages via disulfide formation, the
use of (symmetric) crosslinkers, or the incorporation of non-canonical
amino acids. To facilitate a straightforward cyclization of linear
precursors with asymmetric molecular scaffolds, which are often found
at the core of naturally occurring MPs, we report an efficient two-step
strategy to access MPs via the programmed modification of a unique
cysteine residue and an N-terminal amine. We demonstrate that this
approach yields MPs featuring asymmetric cyclization units from both
synthetic peptides and when linear precursors are appended onto a
phage-coat protein. Finally, we showcase that our cyclization strategy
is compatible with traditional phage-display protocols and enables
the selection of MP binders against a model target protein from naïve
libraries. By enabling the incorporation of non-peptidic moieties
that (1) can serve as cyclization units, (2) provide interactions
for binding, and/or (3) tailor pharmacological properties, our head-to-side-chain
cyclization strategy provides access to a currently under-explored
chemical space for the development of chemical probes and therapeutics
A Strategy to Select Macrocyclic Peptides Featuring Asymmetric Molecular Scaffolds as Cyclization Units by Phage Display
No full textMacrocyclic peptides (MPs) have positioned themselves as a privileged class of compounds for the discovery of therapeutics and development of chemical probes. Aided by the development of powerful selection strategies, high-affinity binders against biomolecular targets can readily be elicited from massive, genetically encoded libraries by affinity selection. For example, in phage display, MPs are accessed on the surface of whole bacteriophages via disulfide formation, the use of (symmetric) crosslinkers, or the incorporation of non-canonical amino acids. To facilitate a straightforward cyclization of linear precursors with asymmetric molecular scaffolds, which are often found at the core of naturally occurring MPs, we report an efficient two-step strategy to access MPs via the programmed modification of a unique cysteine residue and an N-terminal amine. We demonstrate that this approach yields MPs featuring asymmetric cyclization units from both synthetic peptides and when linear precursors are appended onto a phage-coat protein. Finally, we showcase that our cyclization strategy is compatible with traditional phage-display protocols and enables the selection of MP binders against a model target protein from naïve libraries. By enabling the incorporation of non-peptidic moieties that (1) can serve as cyclization units, (2) provide interactions for binding, and/or (3) tailor pharmacological properties, our head-to-side-chain cyclization strategy provides access to a currently under-explored chemical space for the development of chemical probes and therapeutics.</p
The poly(I:C)-induced maternal immune activation model; a systematic review and meta-analysis of cytokine levels in the offspring
No full textThe maternal polyinosinic:polycytidylic acid (poly(I:C)) animal model is frequently used to study how maternal immune activation may impact neuro development in the offspring. Here, we present the first systematic review and meta-analysis on the effects of maternal poly(I:C) injection on immune mediators in the offspring and provide an openly accessible systematic map of the data including methodological characteristics.Pubmed and EMBASE were searched for relevant publications, yielding 45 unique papers that met inclusion criteria. We extracted data on immune outcomes and methodological characteristics, and assessed the risk of bias. The descriptive summary showed that most studies reported an absence of effect, with an equal number of studies reporting an increase or decrease in the immune mediator being studied.Meta-analysis showed increased IL-6 concentrations in the offspring of poly(I:C) exposed mothers. This effect appeared larger prenatally than post-weaning. Furthermore, poly(I:C) administration during mid-gestation was associated with higher IL-6 concentrations in the offspring. Maternal poly(I:C) induced changes in IL-1β, Il-10 and TNF-α concentrations were small and could not be associated with age of offspring, gestational period or sampling location. Finally, quality of reporting of potential measures to minimize bias was low, which stresses the importance of adherence to publication guidelines.Since neurodevelopmental disorders in humans tend to be associated with lifelong changes in cytokine concentrations, the absence of these effects as identified in this systematic review may suggest that combining the model with other etiological factors in future studies may provide further insight in the mechanisms through which maternal immune activation affects neurodevelopment
