Study towards improving artemisinin-based combination therapies.

Covering: Up to 2020 Artemisinin has made a significant contribution towards global malaria control since its initial discovery. Countless lives have been saved by this unique and miraculous molecule. In 2006, artemisinin-based combination therapies (ACTs) were recommended by the World Health Organization (WHO) as the first-line treatment for uncomplicated malaria infection and have since remained as the mainstays of the antimalarial treatment. Even so, substantial efforts to pursue better curative effects for the treatment of malaria have never ceased, particularly with regards to the circumstances surrounding the appearance of delayed clearance of malaria parasites by 3 day ACT treatments in South-East Asian countries. Strategies to further optimize artemisinin-based therapies, including synthesizing better artemisinin derivatives, developing advanced drug delivery systems, and diversifying artemisinin partner drugs, have been proposed over the past few years. Here, we provide an updated account of the continuous efforts in improving ACTs for better efficacy in curing malarial infection.

Genomics-driven discovery of a new cyclodepsipeptide from the guanophilic fungus Amphichorda guana.

Two potential non-ribosomal peptide synthetases (NRPSs) were identified in the genome of a guanophilic fungus Amphichorda guana by bioinformatics analysis and gene knockout experiments. Liquid chromatography coupled with mass spectrometry (LC-MS) guided isolation led to the discovery of a new cyclodepsipeptide isaridin H (1) and seven known analogs, desmethylisaridin E (2), isaridin E (3), isariin A (4), iso-isariin B (5), iso-isariin D (6), isariin E (7), and nodupetide (8). The absolute configuration of isaridin H (1) was achieved by Marfey's method. Isaridin H (1) showed significant antifungal activity against Botrytis cinerea and Alternaria solani.

Heterologous expression of a single fungal HR-PKS leads to the formation of diverse 2-alkenyl-tetrahydropyrans in model fungi.

2-Alkenyl-tetrahydropyrans belong to a rare class of natural products that exhibit broad antifungal activities. Their structural instability and rareness in nature have restrained their discovery and drug development. In this study, the heterologous expression of a single highly reducing polyketide synthase (HR-PKS, App1) from Trichoderma applanatum in Aspergillus nidulans leads to the formation of seven 2-alkenyl-tetrahydropyran derivatives including one known compound virensol C (1) and six new compounds (2-7). However, introducing App1 into Saccharomyces cerevisiae resulted in the identification of additional two 2-alkenyl-tetrahydropyrans lacking the hydroxyl or methoxyl group at the C-2 position (8 and 9). The structures of the isolated compounds were elucidated by extensive spectroscopic analysis using NMR and HR-ESI-MS.

Harnessing diverse transcriptional regulators for natural product discovery in fungi.

Covering: Up to March 2019 Secondary metabolites (SMs) are chemical entities produced by organisms in response to environmental stimuli and as a defense against biological warfare. The production of SMs is controlled by a hierarchical regulatory network involving core factors that orchestrate transcriptional activation of SM gene clusters. In the past few years, significant achievements have been made in the discovery of novel fungal natural products by genetic manipulations of various types of transcriptional regulators. In this review, we summarized the representative regulators for the activation of fungal secondary metabolism and focused on the strategies for the exploitation of these regulators and their application in finding novel structures.

Nitric Oxide Inhibitory Carbazole Alkaloids from the Folk Medicine Murraya tetramera C.C. Huang.

The phytochemical investigation of the leaves and stems of Murraya tetramera C.C. Huang, a traditional folk medicine used as an anti-inflammatory agent, yielded 19 simple carbazole alkaloids, two of which (1-ethoxy-3-methyl-9H-carbazol-2-ol (1) and 7-hydroxy-2,8-dimethoxy-6-methyl-9H-carbazole-1-carbaldehyde (2)) are new ones. The structures of the new compounds were determined by extensive spectroscopic analysis including NMR and HR-EI-MS experiments, as well as comparison with the reported data. Most of the isolates showed potent inhibitory effects on NO production in LPS-stimulated BV-2 microglial cells with IC50 values ranging from 5.1 to 15.1 µM.

Systematic thermal analysis of the Arabidopsis proteome: Thermal tolerance, organization, and evolution.

Understanding the thermal stability of the plant proteome in the context of the native cellular environment would aid the design of crops with high thermal tolerance, but only limited such data are available. Here, we applied quantitative mass spectrometry to profile the thermal stability of the Arabidopsis proteome and identify thermo-sensitive and thermo-resilient protein networks in Arabidopsis, providing a basis for understanding heat-induced damage. We also show that the similarities of the protein-melting curves can be used as a proxy to evaluate system-wide protein-protein interactions in non-engineered plants and enable the identification of transient interactions exhibited by metabolons in the context of the cellular environment. Finally, we report a systematic comparison of the thermal stability of paralogs in Arabidopsis to aid the investigation and understanding of gene duplication and protein evolution. Taken together, our results could have broad implications for the fields of plant thermal tolerance, plant protein assemblies, and evolution.

A new coumarin from Murraya alata activates TRPV1 channel.

One new coumarin, muralatin R, was isolated from the leaves of Murraya alata Drake (Rutaceae). Its structure was elucidated by extensive analysis of the NMR and MS data, along with the specific rotation comparison. Muralatin R was found to be capable of activating the transient receptor potential vanilloid 1 (TRPV1) channel through desensitization mechanism. The results supply reference for clarification of the therapeutic basis and mechanism of action of Murraya plants for treating psychogenic pain or somatoform pain disorders.

Alkaloids from the stems and rhizomes of Sinomenium acutum from the Qinling Mountains, China.

Thirteen undescribed alkaloids (sinotumines A-M), including five oxoisoaporphine, a benzo[h]quinoline, an aporphine, two protoberberine, two hasubanane, and two proaporphine alkaloids, and 50 known analogues were isolated from the 95% aqueous EtOH extract of the stems and rhizomes of Sinomenium acutum. The structures and absolute configurations of the isolates were elucidated on the basis of comprehensive analysis of 1D and 2D NMR, HRMS, single-crystal X-ray diffraction, and comparison of the experimental and calculated electronic circular dichroism (ECD) data. Sinotumine F, a rare benzo[h]quinoline alkaloid, was speculated as an oxidation product of the oxoisoaporphine alkaloid, and its putative biosynthetic pathway is proposed. Sinotumines L and M are the first samples of proaporphine-based heterodimers coupled with 1-heptanone and coniferol alcohol moiety, respectively. The T-cell suppression and NO inhibition effects of the isolates were evaluated.