Poly(hydrophobic Amino Acids) and Liposomes for Delivery of Vaccine against Group A Streptococcus.

Adjuvants and delivery systems are essential components of vaccines to increase immunogenicity against target antigens, particularly for peptide epitopes (poor immunogens). Emulsions, nanoparticles, and liposomes are commonly used as a delivery system for peptide-based vaccines. A Poly(hydrophobic amino acids) delivery system was previously conjugated to Group A Streptococcus (GAS)-derived peptide epitopes, allowing the conjugates to self-assemble into nanoparticles with self adjuvanting ability. Their hydrophobic amino acid tail also serves as an anchoring moiety for the peptide epitope, enabling it to be integrated into the liposome bilayer, to further boost the immunological responses. Polyleucine-based conjugates were anchored to cationic liposomes using the film hydration method and administered to mice subcutaneously. The polyleucine-peptide conjugate, its liposomal formulation, and simple liposomal encapsulation of GAS peptide epitope induced mucosal (saliva IgG) and systemic (serum IgG, IgG1 and IgG2c) immunity in mice. Polyleucine acted as a potent liposome anchoring portion, which stimulated the production of highly opsonic antibodies. The absence of polyleucine in the liposomal formulation (encapsulated GAS peptide) induced high levels of antibody titers, but with poor opsonic ability against GAS bacteria. However, the liposomal formulation of the conjugated vaccine was no more effective than conjugates alone self-assembled into nanoparticles.

Poly(amino acids) as a potent self-adjuvanting delivery system for peptide-based nanovaccines.

To be optimally effective, peptide-based vaccines need to be administered with adjuvants. Many currently available adjuvants are toxic, not biodegradable; they invariably invoke adverse reactions, including allergic responses and excessive inflammation. A nontoxic, biodegradable, biocompatible, self-adjuvanting vaccine delivery system is urgently needed. Herein, we report a potent vaccine delivery system fulfilling the above requirements. A peptide antigen was coupled with poly-hydrophobic amino acid sequences serving as self-adjuvanting moieties using solid-phase synthesis, to produce fully defined single molecular entities. Under aqueous conditions, these molecules self-assembled into distinct nanoparticles and chain-like aggregates. Following subcutaneous immunization in mice, these particles successfully induced opsonic epitope-specific antibodies without the need of external adjuvant. Mice immunized with entities bearing 15 leucine residues were able to clear bacterial load from target organs without triggering the release of soluble inflammatory mediators. Thus, we have developed a well-defined and effective self-adjuvanting delivery system for peptide antigens.

Antioxidant activity and cellular uptake of the hydroxamate-based fungal iron chelators pyridoxatin, desferriastechrome and desferricoprogen.

The hydroxamate class of compounds is well known for its pharmacological applications, especially in the context of chelation therapy. In this work we investigate the performance of the fungal hydroxamates pyridoxatin (PYR), desferriastechrome (DAC) and desferricoprogen (DCO) as mitigators of stress caused by iron overload (IO) both in buffered medium and in cells. Desferrioxamine (DFO), the gold standard for IO treatment, was used as comparison. It was observed that all the fungal chelators (in aqueous medium) or PYR and DAC (in cells) are powerful iron scavengers. However only PYR and DCO (in aqueous medium) or PYR (in cells) were also antioxidant against two forms of iron-dependent oxidative stress (ascorbate or peroxide oxidation). These findings reveal that PYR is an interesting alternative to DFO for iron chelation therapy, since it has the advantage of being cell permeable and thus potentially orally active.

Pursuing sesterterpene lactams in Australian Irciniidae sponges.

Chemical investigation of two Irciniidae sponges collected by hand (SCUBA) from Australian near shore waters, afforded six new examples of a rare class of sesterterpene lactam; ircinialactams B (1), G (2), H (5), and I (6), and 8-hydroxyircinialactams C (3) and G (4); together with the new biosynthetically related lactone, ircinialactone A (7). Also isolated were seven biosynthetically related known Irciniidae metabolites; ircinialactams A (8) and C (9), (7E,12E,20Z,18S)-variabilin (10), (7Z,12Z,20Z,18S)-variabilin (11), (7E,12Z,20Z,18S)-variabilin (12), (7Z,12E,20Z,18S)-variabilin (13) and irciniafuran A (14). The structure elucidation of 1-14 was achieved by detailed spectroscopic analysis, and consideration of a plausible biosynthetic relationship linking Irciniidae sesterterpene ß-furans, lactams and lactones.

Levofloxacin and indolicidin for combination antimicrobial therapy.

Despite the increasing need for antibiotics to fight infectious diseases, fewer new antibiotics are available on the market. Unfortunately, developing a new class of antibiotics is associated with high commercial risk. Therefore, modification or combination of existing antibiotics to improve their efficacy is a promising strategy. Herein, we conjugated the antibiotic, levofloxacin, with two peptides, i.e. an antimicrobial peptide indolicidin and a cell penetrating peptide (TAT). Glycolic acid and glycine linkers were used between levofloxacin and peptides. We developed an optimized condition for coupling of levofloxacin via its carboxylic group to glycolic acid using solid phase peptide synthesis (SPPS). Antibacterial and haemolytic assays were carried out on the conjugates and only the levofloxacin-indolicidin conjugate demonstrated moderate antibacterial activity. Interestingly, physical mixture of levofloxacin and indolicidin showed improvement in the activity against Gram-positive bacteria.

Esmodil: an acetylcholine mimetic resurfaces in a Southern Australian marine sponge Raspailia (Raspailia) sp.

Bioassay directed fractionation of a Raspailia (Raspailia) sp. (Order Poecilosclerida; Family Raspailiidae) collected during scientific trawling operations off the Northern Rottnest Shelf yielded as nematocidal agents the known metabolites, phorboxazoles A (1) and B (2). Further examination revealed the new natural product but known synthetic compound, esmodil (3). The structure for 3 was confirmed by spectroscopic analysis and total synthesis.