Background Human factor XIa (FXIa) is an actively pursued target for development of safer anticoagulants. Our long‐standing hypothesis has been that allosterism originating from heparin‐binding site(s) on coagulation enzymes is a promising approach to yield safer agents. Objectives To develop a synthetic heparin mimetic as an inhibitor of FXIa so as to reduce clot formation in vivo but not carry high bleeding risk. Methods We employed a gamut of methods involving synthetic chemistry, biophysical biochemistry, enzyme assays, blood and plasma coagulation assays, and in vivo thrombosis models in this work. Results Sulfated chiro‐inositol (SCI), a non‐saccharide mimetic of heparin, was synthesized in three steps in overall yields of >50%. SCI inhibited FXIa with potency of 280 nmol/L and preferentially engaged FXIa's heparin‐binding site to conformationally alter its active site. SCI inhibition of FXIa could be rapidly reversed by common antidotes, such as protamine. SCI preferentially prolonged plasma clotting initiated with recalcification, rather than thromboplastin, alluding to its intrinsic pathway‐based mechanism. Human blood thromboelastography indicated good ex vivo anticoagulation properties of SCI. Rat tail bleeding and maximum‐dose‐tolerated studies indicated that no major bleeding or toxicity concerns for SCI suggesting a potentially safer anticoagulation outcome. FeCl3‐induced arterial and thromboplastin‐induced venous thrombosis model studies in the rat showed reduced thrombus formation by SCI at 250 μg/animal, which matched enoxaparin at 2500 μg/animal. Conclusions Overall, SCI is a highly promising, allosteric inhibitor of FXIa that induces potent anticoagulation in vivo. Further studies are necessary to assess SCI in animal models mimicking human clinical indications.

Heparanase, an endo-β-D-glucuronidase, cleaves cell surface and extracellular matrix heparan sulfate (HS) chains and plays important roles in cellular growth and metastasis. Heparanase assays reported to-date are labor intensive, complex and/or expensive. A simpler assay is critically needed to understand the myriad roles of heparanase. We reasoned that fluorescent heparin could serve as an effective probe of heparanase levels. Following synthesis and screening, a heparin preparation labeled with DABCYL and EDANS was identified, which exhibited a characteristic increase in signal following cleavage by human heparanase. This work describes the synthesis of this heparin substrate, its kinetic and spectrofluorometric properties, optimization of the heparanase assay, use of the assay in inhibitor screening, and elucidation of the state of heparanase in different cell lines. Our FRET-based assay is much simpler and more robust than all assays reported in the literature as well as a commercially available kit.

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There is a unique microbial community in the female lower genital tract known as the vaginal microbiota, which varies in composition and density and provides significant benefits during pregnancy, reproductive cyclicity, healthy newborn delivery, protection from preterm birth, infections such as UTIs, bacterial vaginosis, and so on, and improves the efficacy of treatments for vaginal cancers. Methods: It is necessary to know how the vaginal microbiome is composed in order to make an accurate diagnosis of the diseases listed above. A microbiome’s members are difficult to classify, and the way microbial communities function and influence host–pathogen interactions are difficult to understand. More and more metagenomic studies are able to unravel such complexities due to advances in high-throughput sequencing and bioinformatics. When it comes to vaginal microbiota research, we’ll be looking at the use of modern techniques and strategies that can be used to investigate variations in vaginal microbiota in order to detect diseases earlier, better treat vaginal disorders, and boost women’s health. Discussion: The discussed techniques and strategies may improve the treatment of vaginal disorders and may be beneficial for women’s overall health.

The insulin-like growth factor-1 receptor (IGF-1R) is a receptor tyrosine kinase (RTK) that plays critical roles in cancer. Microarray, computational, thermodynamic, and cellular imaging studies reveal that activation of IGF-1R by its cognate ligand IGF1 is inhibited by shorter, soluble heparan sulfate (HS) sequences (e.g., HS06), whereas longer polymeric chains do not inhibit the RTK, a phenomenon directly opposed to the traditional relationship known for GAG-protein systems. The inhibition arises from smaller oligosaccharides binding in a unique pocket in the IGF-1R ectodomain, which competes with the natural cognate ligand IGF1. This work presents a highly interesting observation on preferential and competing inhibition of IGF-1R by smaller sequences, whereas polysaccharides are devoid of this function. These insights will be of major value to glycobiologists and anti-cancer drug discoverers.