Growth factor (GF)
signaling is a key determinant of stem cell
fate. Interactions of GFs with their receptors are often mediated
by heparan sulfate proteoglycans (HSPGs). Here, we report a cell surface
engineering strategy that exploits the function of HSPGs to promote
differentiation in embryonic stem cells (ESCs). We have generated
synthetic neoproteoglycans (neoPGs) with affinity for the fibroblast
growth factor 2 (FGF2) and introduced them into plasma membranes of
ESCs deficient in HS biosynthesis. There, the neoPGs assumed the function
of native HSPGs, rescued FGF2-mediated kinase activity, and promoted
neural specification. This glycocalyx remodeling strategy is versatile
and may be applicable to other types of differentiation.
(group B , GBS) is a leading cause of invasive bacterial infections in newborns, typically acquired vertically during childbirth secondary to maternal vaginal colonization. Human milk oligosaccharides (HMOs) have important nutritional and biological activities that guide the development of the immune system of the infant and shape the composition of normal gut microbiota. In this manner, HMOs help protect against pathogen colonization and reduce the risk of infection. In the course of our studies of HMO-microbial interactions, we unexpectedly uncovered a novel HMO property to directly inhibit the growth of GBS independent of host immunity. By separating different HMO fractions through multidimensional chromatography, we found the bacteriostatic activity to be confined to specific non-sialylated HMOs and synergistic with a number of conventional antibiotic agents. Phenotypic screening of a GBS transposon insertion library identified a mutation within a GBS-specific gene encoding a putative glycosyltransferase that confers resistance to HMOs, suggesting that HMOs may function as an alternative substrate to modify a GBS component in a manner that impairs growth kinetics. Our study uncovers a unique antibacterial role for HMOs against a leading neonatal pathogen and expands the potential therapeutic utility of these versatile molecules.
We investigated the antimicrobial activities of N-substituted glycine "peptoid" oligomers incorporating cationic and hydrophobic side chains. Head-to-tail macrocyclization was employed to enhance antimicrobial activity. Both linear and cyclic peptoids, ranging from six to ten residues, demonstrate potent antimicrobial activity against Gram-positive and Gram-negative bacteria. These peptoids do not cause significant lysis of human erythrocytes, indicating selective antimicrobial activity. Conformational ordering established upon macrocyclization is generally associated with an enhanced capacity to inhibit bacterial cell growth. Moreover, increased hydrophobic surface area also plays a role in improving antimicrobial activity. We demonstrate the potency of a cyclic peptoid in exerting antimicrobial activity against clinical strains of S. aureus while deterring the emergence of antimicrobial resistance.
Macrocyclic constraints are often employed to rigidify the conformation of flexible oligomeric systems. This approach has recently been used to organize the structure of peptoid oligomers, which are peptidomimetics composed of chemically diverse N-substituted glycine monomer units. In this review, we describe advances in the synthesis and characterization of cyclic peptoids. We evaluate how the installation of covalent constraints between the oligomer termini or side chains has been effective in defining peptoid conformations. We also discuss the potential applications for this promising family of macrocyclic peptidomimetics.
Influenza viruses bind to mucosal glycans to gain entry into a host organism and initiate infection. The target glycans are often displayed in multivalent arrangements on proteins; however, how glycan presentation influences viral specificity is poorly understood. Here, we report a microarray platform approximating native glycan display to facilitate such studies.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.