Safety and parasite clearance of artemisinin-resistant Plasmodium falciparum infection: A pilot and a randomised volunteer infection study in Australia.

Background: Artemisinin resistance is threatening malaria control. We aimed to develop and test a human model of artemisinin-resistant (ART-R) Plasmodium falciparum to evaluate the efficacy of drugs against ART-R malaria.

Methods And Findings: We conducted 2 sequential phase 1, single-centre, open-label clinical trials at Q-Pharm, Brisbane, Australia, using the induced blood-stage malaria (IBSM) model, whereby healthy participants are intravenously inoculated with blood-stage parasites.

Cyclic peptides arising by evolutionary parallelism via asparaginyl-endopeptidase-mediated biosynthesis.

The cyclic miniprotein Momordica cochinchinensis Trypsin Inhibitor II (MCoTI-II) (34 amino acids) is a potent trypsin inhibitor (TI) and a favored scaffold for drug design. We have cloned the corresponding genes and determined that each precursor protein contains a tandem series of cyclic TIs terminating with the more commonly known, and potentially ancestral, acyclic TI. Expression of the precursor protein in Arabidopsis thaliana showed that production of the cyclic TIs, but not the terminal acyclic TI, depends on asparaginyl endopeptidase (AEP) for maturation.

Identification and characterization of a new family of cell-penetrating peptides: cyclic cell-penetrating peptides.

Cell-penetrating peptides can translocate across the plasma membrane of living cells and thus are potentially useful agents in drug delivery applications. Disulfide-rich cyclic peptides also have promise in drug design because of their exceptional stability, but to date only one cyclic peptide has been reported to penetrate cells, the Momordica cochinchinensis trypsin inhibitor II (MCoTI-II). MCoTI-II belongs to the cyclotide family of plant-derived cyclic peptides that are characterized by a cyclic cystine knot motif.

Naturally occurring circular proteins: distribution, biosynthesis and evolution.

Circular proteins, i.e., proteins with a backbone comprised of a continuous and seamless circle of amino acids, have been discovered over the last 15 years in bacteria, plants, fungi and animals.

Nanoconjugates as intracorporeal neutralizers of bacterial endotoxins.

Sepsis is a leading cause of mortality that is most often provoked by endotoxins (i.e. lipopolysaccharides; LPS) released by Gram-negative bacteria into the patient's bloodstream during infection.

Design and facile solid-phase synthesis of peptide-based LPS-inhibitors containing PEG-like functionalities.

LPS release from Gram-negative bacteria can result in sepsis, a serious systemic inflammatory response to infection that can lead to septic shock and multiple organ failure. Thus, easy-to-synthesize, effective, and safe LPS-inhibitors are required to develop new agents for the treatment of sepsis. On the basis of the chemical features of the toxic part of LPS, lipid A, here we present peptide-based LPS-neutralizers that can be readily obtained using solid-phase methodologies.

Tiratricol neutralizes bacterial endotoxins and reduces lipopolysaccharide-induced TNF-alpha production in the cell.

The screening of a commercially available library of compounds has proved a successful strategy for the identification of a lead compound in a drug discovery programme. Here, we analysed 880 off-patent drugs, which initially comprised the Prestwick Chemical library, as sources of bacterial endotoxin neutralizers. We identified 3,3',5-triiodo-thyroacetic acid (tiratricol) as a non-antibacterial compound that neutralizes the toxic lipopolysaccharide.

Nanostructure formation enhances the activity of LPS-neutralizing peptides.

Peptides that interact with lipopolysaccharide (LPS) can provide the basis for the development of new antisepsis agents. In this work, several LPS-neutralizing acyl peptides derived from LALF, BPI, and SAP were prepared, structurally characterized, and biologically evaluated. In all cases, peptides with long acyl chains showed greater LPS-neutralizing activities than the original acetylated peptides.