Disulfide bridge-targeted metabolome mining unravels an antiparkinsonian peptide

Peptides are a particular molecule class with inherent attributes of some small-molecule drugs and macromolecular biologics,thereby inspiring continuous searches for peptides with therapeutic and/or agrochemical potentials.However,the success rate is decreasing,presumably because many interesting but less-abundant peptides are so scarce or labile that they are likely‘overlooked’during the characterization effort.Here,we present the biochemical characterization and druggability improvement of an unprecedented minor fungal RiPP(ribosomally synthesized and post-translationally modified peptide),named acalitide,by taking the relevant advantages of metabolomics approach and disulfide-bridged substructure which is more frequently imprinted in the marketed peptide drug molecules.Acalitide is biosynthetically unique in the macrotricyclization via two disulfide bridges and a protease(AcaB)-catalyzed lactamization of AcaA,an unprecedented precursor peptide.Such a biosynthetic logic was successfully re-edited for its sample supply renewal to facilitate the identification of the in vitro and in vivo antiparkinsonian efficacy of acalitide which was further confirmed safe and rendered brain-targetable by the liposome encapsulation strategy.Taken together,the work updates the mining strategy and biosynthetic complexity of RiPPs to unravel an antiparkinsonian drug candidate valuable for combating Parkinson’s disease that is globally prevailing in an alarming manner.

Identification of highly efficacious PROTACs targeting BRD4 against acute myeloid leukemia:Design,synthesis,and biological evaluations

The abnormal activation of BRD4 accelerates the progression of acute myeloid leukemia(AML),developing more precise therapeutics to intervene BRD4 promise to be an excellent opportunity to avoid current limitations of chemotherapy in clinic.Herein,a range of small-molecule PROTACs with the privileged 8-methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one scaffold were rationally designed,which harbored different carbon or ethylenedioxy chains to degrade BRD4 mediated by the E3 ubiquitin ligase CRBN.Among them,the most potential B24 exhibited remarkable BRD4 degradation and excellent anti-proliferative activities in MV4-11 cells,with values of DC_(50)and IC_(50)for 0.75 nmol/L and 0.4 nmol/L,respectively,which were better than the BRD4 inhibitor(+)-JQ-1.Notably,this compound could time-dependently degrade the target protein in the BRD4-,CRBN-,and proteasome-dependent manner.Besides,B24 dramatically decreased the level of proto-oncogene c-Myc,and induced cell apoptosis by arresting the cell cycle in G0/G1 phase,down-regulating Bcl-2 and up-regulating Bax to amplify apoptotic effectors.This proof-of-concept study also highlighted the feasibility of BRD4-based PROTACs as a more powerful strategy against AML.

Cytotoxic and antibacterial polyketide-indole hybrids synthesized from indole-3-carbinol by Daldinia eschscholzii

Two skeletally undescribed polyketide-indole hybrids(PIHs), named indolchromins A and B,were generated from indole-3-carbinol(I3 C) in the fungal culture(Daldinia eschscholzii). The indolchromin structures were elucidated mainly by their 1 D and 2 D NMR spectra with the former confirmed by the single-crystal X-ray crystallographic analysis. Each indolchromin alkaloid was chirally separated into four isomers, whose absolute configurations were assigned by comparing the recorded circular dichroism(CD) spectra with the electronic CD(ECD) curves computed for all optional stereoisomers. Furthermore, the indolchromin construction pathways in fungal culture were clarified through enzyme inhibition, precursor feeding experiment, and energy calculation. The cascade reactions,including decarboxylative Claisen condensation catalyzed by 8-amino-7-oxononanoate synthase(AONS),C(sp3)-H activation, double bond migration, and Michael addition, all undergone compatibly during the fungal cultivation. In an MIC range of 1.3–8.6 μmol/L,(2 S,4 R)-and(2 R,4 S)-indolchromin A and(2 R,4 S)-indolchromin B are inhibitory against Clostridium perfringens, Clostridium difficile, Veillonella sp.,Bacteroides fragilis, and Streptococcus pyogenes.(2 R,4 S)-Indolchromin A and(2 S,4 S)-indolchromin B were cytotoxic against the human breast cancer cell line MDA-MB-231 with IC50 values of 27.9 and131.2 nmol/L, respectively, with the former additionally active against another human breast cancer cell line MCF-7(IC_(50)94.4 nmol/L).

Chartrenoline, a novel alkaloid isolated from a marine Streptomyces chartreusis NA02069

A novel alkaloid, chartrenoline(1), featuring an unusual 6/6/5/5-tetracyclic nucleus, was isolated from a marine Streptomyces chartreusis NA02069. The structure of 1 including its absolute configurations was established by extensive analyses of its high resolution mass, NMR and single-crystal X-ray diffraction data. A plausible biosynthetic pathway for chartrenoline(1) is proposed.

Symbionts, a promising source of bioactive natural products

Symbionts are microorganisms residing in multicellular hosts(e.g., plants and animals), and they have been witnessed to be a rich source of diverse functional molecules. This review describes structures and biological activities of symbiont-derived secondary metabolites commonly referred to as "natural products", and highlights that symbiotic microbes represent an underexplored reservoir of natural products with unique scaffolds and promising significance in managing human healthcare and agricultural production.

Anti-inflammatory spirobisnaphthalene natural products from a plant-derived endophytic fungus Edenia gomezpompae

Spirobisnaphthalenes comprise a relatively rare family of natural products that are normally isolated from fungi and occasionally from plants.Here we reported the discovery of seven new preussomerintype spirobisnaphthalenes,preussomerins YT1-YT7(1-7),and seven known ones(8-14),from the endophytic fungus Edenia gomezpompae,enriching the structural diversity of this family of natural products.Their structures were established by 1 D and 2 D NMR spectroscopy,HRESIMS analysis and comparison with previously reported compounds,with the absolute configurations of compounds 1 and2 being further confirmed by single-crystal X-ray diffraction using Cu Ka radiation.The antiinflammatory activities of all isolates were assessed by measuring the production of NO in LPS-induced RAW264.7 macrophage cells.Among them,compounds 8 and 13 exhibited potent inhibitory activities on the production of NO,with IC50 values of 2.61 and 1.32μmol/L,respectively.