Single-entity heparan sulfate glycomimetic clusters for therapeutic applications

Heparan sulfate (HS) is a highly sulfated glycosaminoglycan with a variety of critical functions in cell signaling and regulation. HS oligosaccharides can mimic or interfere with HS functions in biological systems; however, their exploitation has been hindered by the complexity of their synthesis. Polyvalent displays of small specific HS structures on dendritic cores offer more accessible constructs with potential advantages as therapeutics, but the synthesis of single-entity HS polyvalent compounds has not previously been described. Herein we report the synthesis of a novel targeted library of single-entity glycomimetic clusters capped with varied HS saccharides. They have the ability to mimic longer natural HS saccharides in their inhibition of the Alzheimer's disease (AD) protease BACE-1. We have identified several single-entity HS clusters with IC50 values in the low-nanomolar range. These HS clusters are drug leads for AD and offer a novel framework for the manipulation of heparan sulfate-protein interactions in general

Crystal packing in three related disaccharides: Precursors to heparan sulfate oligosaccharides

The three title compounds form part of a set of important precursor dissacharides which lead to novel therapeutics, in particular for Alzheimer's disease. All three crystallize as poorly diffracting crystals with one independent molecule in the asymmetric unit. Two of them are isostructural: 4-methoxyphenyl 4-O-[6-O-acetyl-2-azido-3-O-benzyl-2-deoxy-4-O-(9-fluorenylmethyloxycarbonyl)-α-D-glucopyranosyl]-2-O-benzoyl-3-O-benzyl-6-O-chloroacetyl-α-L-idopyranoside, C59H56ClN3O16, (I), the ido-relative of a reported gluco-disaccharide [Gainsford et al., 2013). Acta Cryst. C69, 679-682] and 4-methoxyphenyl 4-O-[6-O-acetyl-2-azido-3-O-benzyl-2-deoxy-4-O-(9-fluorenylmethyloxycarbonyl)-α-D-glucopyranosyl]-2-O-benzoyl-3-O-benzyl-6-O-methoxyacetyl-α-L-idopyranoside, C60H59N3O17, (II). Both exhibit similar conformational disorder of pendant groups. The third compound 4-methoxyphenyl 4-O-[6-O-acetyl-2-azido-3,4-di-O-benzyl-2-deoxy-α-D-glucopyranosyl]-2-O-benzoyl-3-O-benzyl-6-O-methoxyoacetyl-β-D-glucopyranoside, C52H55N3O15, (III), illustrates that a slightly larger set of weak intermolecular interactions can result in a less disordered molecular arrangement. The molecules are bound by weak C-H⋯O(ether) hydrogen bonds in (I) and (II), augmented by C-H⋯π interactions in (III). The absolute configurations were determined, although at varying levels of significance from the limited observed data

Composition, sequencing and ion mobility mass spectrometry of heparan sulfatelike octasaccharide isomers differing in glucuronic and iduronic acid content

Here we report ion mobility mass spectrometry (IMMS) separation and tandem mass spectrometry (MS2) sequencing methods used to analyze and differentiate six synthetically produced heparin/heparan sulfate (HS)-like octasaccharide (dp8) isomeric structures. These structures are isomeric with regard to either glucuronic acid (GlcA) or iduronic acid (IdoA) residues at various positions. IMMS analysis showed that a fully GlcA structure exhibited a more compact conformation, whereas the fully IdoA structure was more extended. Interestingly, the change from IdoA to GlcA in specific locations resulted in strong conformational distortions. MS2 of the six isomers showed very different spectra with unique sets of diagnostic product ions. Analysis of MS2 product ion spectra suggests that the GlcA group correlated with the formation of a glycosidic product ion under lower energy conditions. This resulted in an earlier product ion formation and more intense product ions. Importantly, this knowledge enabled a complete sequencing of the positions of GlcA and IdoA in each of the four positions located in each unique dp8 structure

Metabolic dependency of chorismate in Plasmodium falciparum suggests an alternative source for the ubiquinone biosynthesis precursor

The shikimate pathway, a metabolic pathway absent in humans, is responsible for the production of chorismate, a branch point metabolite. In the malaria parasite, chorismate is postulated to be a direct precursor in the synthesis of p-aminobenzoic acid (folate biosynthesis), p-hydroxybenzoic acid (ubiquinone biosynthesis), menaquinone, and aromatic amino acids. While the potential value of the shikimate pathway as a drug target is debatable, the metabolic dependency of chorismate in P. falciparum remains unclear. Current evidence suggests that the main role of chorismate is folate biosynthesis despite ubiquinone biosynthesis being active and essential in the malaria parasite. Our goal in the present work was to expand our knowledge of the ubiquinone head group biosynthesis and its potential metabolic dependency on chorismate in P. falciparum. We systematically assessed the development of both asexual and sexual stages of P. falciparum in a defined medium in the absence of an exogenous supply of chorismate end-products and present biochemical evidence suggesting that the benzoquinone ring of ubiquinones in this parasite may be synthesized through a yet unidentified route

The post-lockdown period should be used to acquire effective therapies for future resurgence in SARS-Cov-2 infections.

COVID-19 will be with us through the remainder of 2020 and almost certainly beyond. New Zealand needs a viable strategy to protect its populace until a vaccine is developed and in wide use. Until that time, it makes sense to protect the population by putting in place treatments that will be safe and effective, such as the use of convalescent sera and the use of direct-acting anti-virals. These treatments should be sourced externally or made locally, but steps in this direction must now begin as the lockdown ends. New Zealand has the scientists, the facilities and the will to make this happen, but the support of the government and the population will be needed if this plan is to succeed