Sugars Require Rigid Multivalent Displays for Activation of Mouse Sperm Acrosomal Exocytosis

Abstract

As a prerequisite to mammalian fertilization, the sperm acrosomal vesicle fuses with the plasma membrane and the acrosome contents are exocytosed. Induction occurs through engagement of the sperm receptors by multiple sugar residues. Multivalent polymers displaying mannose, fucose, or GlcNAc are effective synthetic inducers of mouse sperm acrosomal exocytosis (AE). Each carbohydrate is proposed to have a distinct binding site on the sperm cell surface. To determine the role of the scaffold structure in the efficiency of AE induction, different polymer backbones were employed to display the different activating sugar residues. These glycopolymers were prepared by ruthenium-catalyzed ring-opening metathesis of 5-substituted norbornene or cyclooctene. The conformations of the glycopolymers were characterized by small-angle X-ray scattering. Polynorbornene displaying mannose, fucose, or GlcNAc forms flexible cylinders in aqueous solution. However, polycyclooctenes displaying any of these same sugars are much more flexible and form random coils. The flexible polycyclooctenes displaying fucose or GlcNAc were less effective inducers of AE than their norbornene counterparts. In contrast, polycyclooctene displaying mannose was the most effective AE inducer and had a more collapsed spherelike structure. Our results suggest that the AE efficacy of fucose, GlcNAc, and mannose polymers relies on a relatively rigid polymer that can stabilize receptor signaling complexes.

Glycopolymers Prepared by Alternating Ring-Opening Metathesis Polymerization Provide Access to Distinct, Multivalent Structures for the Probing of Biological Activity

“…The slope at low-q approaches 0 for all of the polymers, indicating that there are defined freefloating scattering particles in solution. Based on the slope of the curves, poly(1) 100 and poly(1) 50 were fit to a flexible cylinder model (Figure 3A), which is consistent with our previously reported data on norbornene homopolymers, 25 and the fits for polymers with a norbornene backbone were performed by others. 32−34 The flexible cylinder model contains the physical parameters: length, Kuhn length, and radius.…”

Triblock Glycopolymers with Two 10-mer Blocks of Activating Sugars Enhance the Activation of Acrosomal Exocytosis in Mouse Sperm

“…As previously stated, mannose and fucose moieties paired with a polynorbornene backbone were found to be potent inducers of AE in mouse sperm; in particular, when tested over a wide range of polymer concentrations, these sugars were shown to have the highest AE% along with the lowest EC 50 values . As a result, mannose and fucose were designated as the activating sugars while glucose was employed as a nonactivating sugar because it does not induce AE in mouse sperm. ,, In addition to the identity of the sugars, the placement of these moieties was considered. Our goal was to prepare sequence-specific polymers that would elucidate the polymer architecture necessary for the activation of AE as well as provide additional information about the receptors on the sperm involved in AE.…”

Design of biomaterials through direct ring-opening metathesis polymerisation of functionalised cyclic alkenes

“…In 2017, Sampson et al reported the ROMP of monomers substituted with l -fucose, d -mannose, N -acetyl- d -glucosamine ( d -GlcNAc), and d -glucose for carboxylic acids introduced at the 4-position of cyclooctene 168 (Fig. 15).…”