Jeffrey M. Rose

Semicrystalline thermoplastic elastomeric polyolefins: Advances through catalyst development and macromolecular design

We report the design, synthesis, morphology, phase behavior, and mechanical properties of semicrystalline, polyolefin-based block copolymers. By using living, stereoselective insertion polymerization catalysts, syndiotactic polypropylene-block-poly(ethylene-co-propylene)-block-syndiotactic polypropylene and isotactic polypropylene-block-regioirregular polypropylene-block-isotactic polypropylene triblock copolymers were synthesized. The volume fraction and composition of the blocks, as well as the overall size of the macromolecules, were controlled by sequential synthesis of each block of the polymers. These triblock copolymers, with semicrystalline end-blocks and mid-segments with low glass-transition temperatures, show significant potential as thermoplastic elastomers. They have low Youngs moduli, large strains at break, and better than 90% elastic recovery at strains of 100% or less. An isotactic polypropylene-block-regioirregular polypropylene-block-isotactic polypropylene-block-regioirregular polypropylene-block-isotactic polypropylene pentablock copolymer was synthesized that also shows exceptional elastomeric properties. Notably, microphase separation is not necessary in the semicrystalline isotactic polypropylenes to achieve good mechanical performance, unlike commercial styrenic thermoplastic elastomers.

Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria

Excessive release of proinflammatory cytokines by innate immune cells is an important component of the pathogenic basis of malaria. Proinflammatory cytokines are a direct output of Toll-like receptor (TLR) activation during microbial infection. Thus, interference with TLR function is likely to render a better clinical outcome by preventing their aberrant activation and the excessive release of inflammatory mediators. Herein, we describe the protective effect and mechanism of action of E6446, a synthetic antagonist of nucleic acid-sensing TLRs, on experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA. We show that in vitro, low doses of E6446 specifically inhibited the activation of human and mouse TLR9. Tenfold higher concentrations of this compound also inhibited the human TLR8 response to single-stranded RNA. In vivo, therapy with E6446 diminished the activation of TLR9 and prevented the exacerbated cytokine response observed during acute Plasmodium infection. Furthermore, severe signs of ECM, such as limb paralysis, brain vascular leak, and death, were all prevented by oral treatment with E6446. Hence, we provide evidence that supports the involvement of nucleic acid-sensing TLRs in malaria pathogenesis and that interference with the activation of these receptors is a promising strategy to prevent deleterious inflammatory responses that mediate pathogenesis and severity of malaria.

Safety, Pharmacokinetics, Pharmacodynamics, and Plasma Lipoprotein Distribution of Eritoran (E5564) during Continuous Intravenous Infusion into Healthy Volunteers

ABSTRACT Eritoran, a structural analogue of the lipid A portion of lipopolysaccharide (LPS), is an antagonist of LPS in animal and human endotoxemia models. Previous studies have shown that low doses (350 to 3,500 μg) of eritoran have demonstrated a long pharmacokinetic half-life but a short pharmacodynamic half-life. The present study describes the safety, pharmacokinetics and pharmacodynamics, and lipid distribution profile of eritoran during and after a 72-h intravenous infusion of 500, 2,000, or 3,500 μg/h into healthy volunteers. Except for the occurrence of phlebitis, eritoran administration over 72 h was safe and well tolerated. Eritoran demonstrated a slow plasma clearance (0.679 to 0.930 ml/h/kg of body weight), a small volume of distribution (45.6 to 49.8 ml/kg), and a relatively long half-life (50.4 to 62.7 h). In plasma, the majority (∼55%) of eritoran was bound to high-density lipoproteins. During infusion and for up to 72 h thereafter, ex vivo response of blood to 1- or 10-ng/ml LPS was inhibited by ≥85%, even when the lowest dose of eritoran (500 μg/h) was infused. Inhibition of response was dependent on eritoran dose and the concentration of LPS used as an agonist. Finally, in vitro analysis with purified lipoprotein and protein fractions from plasma obtained from healthy volunteers indicated that eritoran is inactivated by high-density but not low-density lipoproteins, very-low-density lipoproteins, or albumin. From these results, we conclude that up to 252 mg of eritoran can be safely infused into normal volunteers over 72 h and even though it associates extensively with high-density lipoproteins, antagonistic activity is maintained, even after infusion ceases.

Novel synthetic LPS receptor agonists boost systemic and mucosal antibody responses in mice.

Safe and cost-effective adjuvants are a critical requirement for subunit vaccine development. We report here the in vivo activity of a series of fully synthetic LPS receptor agonists that have been shown to activate NF-kappaB signaling through the Toll-like receptor 4 (TLR4). These compounds boost antibody responses to protein antigens when coadministered at microgram doses in mice. At these dosage levels no adverse effects are observed. Antibody responses are largely IgG1, with enhanced IgG2a, and down-regulated IgE as compared to alum adjuvanted immunization. Stimulation of Th1 is confirmed by enhanced gamma-interferon production after in vitro antigen restimulation of spleen cells from mice immunized with the synthetic adjuvants. The adjuvants are active by both subcutaneous and intranasal routes of vaccine administration, and in the latter case can amplify both serum IgG and serum and mucosal IgA responses. The compounds must be administered at the same site with antigen to boost anti-vaccine antibody. These fully synthetic ligands of the innate immune system offer the potential for use as effective, safe, and nonbiologically-derived adjuvants.

Synthesis of Semicrystalline Polyolefin Materials: Precision Methyl Branching via Stereoretentive Chain Walking

We report the discovery of C2-symmetric nickel catalysts capable of the regio- and isoselective polymerization of 1-butene to produce isotactic 4,2-poly(1-butene), a new semi-crystalline polyolefin. The catalyst exhibits enantioface selectivities as high as 84% and the resulting polymers display melting temperatures up to 86 °C. This system marks a rare example of preserving stereochemistry through a chain walking polymerization process.