Redox Homeostasis within the Drug-Resistant Malarial Parasite Digestive Vacuole.

We have developed a cost-effective strategy for the complete synthesis of azetidinyl coumarin fluorophore derivatives that report changes in physiologic levels of glutathione (GSH), which includes a more cost- effective synthesis of the probe precursor hydroxyl derivative and its subsequent derivatization to promote subcellular localization. We functionalize coumarin derivatives with a cyano side chain similar to a previous strategy (Jiang X. et al.

Additional PfCRT mutations driven by selective pressure for improved fitness can result in the loss of piperaquine resistance and altered physiology.

Our study leverages gene editing techniques in asexual blood stage parasites to profile novel mutations in mutant PfCRT, an important mediator of piperaquine resistance, which developed in Southeast Asian field isolates or in parasites cultured for long periods of time. We provide evidence that increased parasite fitness of these lines is the primary driver for the emergence of these PfCRT variants. These mutations differentially impact parasite susceptibility to piperaquine and chloroquine, highlighting the multifaceted effects of single point mutations in this transporter.

Structures of Chloroquine Resistance Transporter (PfCRT) Isoforms and Their Interactions with Chloroquine.

Using a recently elucidated atomic-resolution cryogenic electron microscopy (cryo-EM) structure for the chloroquine resistance transporter (PfCRT) protein 7G8 isoform as template [Kim, J.; 2019, 576, 315-320], we use Monte Carlo molecular dynamics (MC/MD) simulations of PfCRT embedded in a 1-palmitoyl-2-oleoyl--glycero-3-phosphocholine (POPC) membrane to solve energy-minimized structures for 7G8 PfCRT and two additional PfCRT isoforms that harbor 5 or 7 amino acid substitutions relative to 7G8 PfCRT. Guided by drug binding previously defined using chloroquine (CQ) photoaffinity probe labeling, we also use MC/MD energy minimization to elucidate likely CQ binding geometries for the three membrane-embedded isoforms.

Artemisinin-Based Drugs Target the Plasmodium falciparum Heme Detoxification Pathway.

Artemisinin (ART)-based antimalarial drugs are believed to exert lethal effects on malarial parasites by alkylating a variety of intracellular molecular targets. Recent work with live parasites has shown that one of the alkylated targets is free heme within the parasite digestive vacuole, which is liberated upon hemoglobin catabolism by the intraerythrocytic parasite, and that reduced levels of heme alkylation occur in artemisinin-resistant parasites. One implication of heme alkylation is that these drugs may inhibit parasite detoxification of free heme via inhibition of heme-to-hemozoin crystallization; however, previous reports that have investigated this hypothesis present conflicting data.

β-Strand inspired bifacial π-conjugated polymers.

Access to diverse, relatively high molecular weight soluble linear polymers without pendant solubilizing chains is the key to solution state synthesis of structurally diverse nanoribbons of conjugated materials. However, realizing soluble 1D-π-conjugated polymers without pendant solubilizing chains is a daunting task. Herein, inspired from the polypeptide β-strand architecture, we have designed and developed novel bifacial π-conjugated polymers ( : 24 kDa) that are soluble ( 70 to >250 mM) despite the absence of pendant solubilizing chains.

A practical diastereoselective synthesis of (-)-bestatin.

Diastereoselective addition of nitromethane to Boc-D-Phe-H in the presence of sodium hydride in diethyl ether/hexane containing 15-crown-5 and subsequent N,O-protection with 2,2-dimethoxypropane gave trans-oxazolidine in a diastereomeric ratio of >16:1. The oxazolidine was easily separated by column chromatography, which after Nef reaction was coupled to H-Leu-OtBu. The 8-step synthesis afforded (-)-bestatin in an overall yield of 24.

Modified primers for rapid and direct electrochemical analysis of coeliac disease associated HLA alleles.

Direct detection of PCR product via hybridisation assay, would facilitate the development of rapid tools for genetic analysis. Here, a PCR primer designed to generate a PCR amplicon tagged with single stranded DNA tails at each end of the duplex, which can be used for direct hybridisation with a surface immobilised probe and an enzyme labelled reporter probe is presented. Four modified sequence specific primers (SSP) pairs were designed for the selective amplification of coeliac disease associated alleles (DQA1*05, DQB1*02, DQB1*03:02 alleles), and human growth hormone (positive control).