In This Issue Cite This: ACS Med. Chem. Lett. 2019, 10, 142−142
Downloaded via 83.171.253.254 on February 14, 2019 at 08:34:40 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
■
RAPID DISCOVERY OF POTENT AND SELECTIVE ZIKV NS2B-NS3 PROTEASE INHIBITORS Arthropod-borne viruses (arboviruses) are a large group of human pathogens to which the Zika virus (ZIKV) belongs. The WHO declared a public health emergency in 2016 due to outbreaks in several countries and birth defects observed in babies from mothers who had contracted the virus during pregnancy. With the threat of new epidemics just around the corner and limited treatment options, continued efforts are necessary to identify selective antivirals. In the present Featured Letter, Nitsche and colleagues (DOI: 10.1021/acsmedchemlett.8b00535) report the identification of novel macrocyclic inhibitors of the ZIKV NS2BNS3 Protease. Using a display screening approach called Random nonstandard Peptide Integrated Discovery (RaPID), different libraries of unnatural peptides were synthesized and tested against the target enzyme. The authors discovered six novel compounds with nanomolar affinities. Five of these compounds exhibited potent protease inhibition, and two displayed selectivity for the ZIKV NS2B-NS3 protease over related proteases from other viruses. Mechanistic studies demonstrated a noncompetitive synergistic effect in the presence of the covalent inhibitor cn-716, suggesting that these compounds might act as allosteric inhibitors and making them valuable hits for further studies.
enhanced potency against RXR and ultimately resulted in discovery of the highly selective compound 28. Overall, this work paves the way for further design of novel RXR agonists characterized by improved in vitro ADME properties and with potential applications in cancer, inflammation and neurodegenerative diseases.
■
MAKING DRUGS FROM TOXINS: IDENTIFICATION OF PORTIMINE B AS POTENT CHEMOTHERAPEUTIC AGENT FOR THE TREATMENT OF ORAL SQUAMOUS CARCINOMA Natural metabolites are an exceptional inventory of highly diversified scaffolds with valuable biological activities. Spiroimines are a family of macrocyclic toxins produced by marine dinoflagellates that exhibit promising therapeutic potential. Portimine is a particularly interesting spiroimine because of its potent anticancer activity and favorable toxicity profile. Herein, Fribley et al. (10.1021/acsmedchemlett.8b00473) focus their work on the isolation and structural characterization of novel spiroimine derivatives. The authors performed a metabolomics analysis of cultures of dinoflagellates to evaluate the diversity of spiroimines produced and to identify novel analogs. S-plot analysis of metabolites produced from V. rugosum highlighted the presence of an unknown compound closely related to portimine. The metabolite was separated and its structure thoroughly characterized by HRESIMS and NMR spectroscopy. The newly discovered compound, named Portimine B, was tested for its ability to passively diffuse through lipid membranes via parallel artificial membrane permeability assays and further studied on two human oral cavity squamous carcinoma cell lines. The in vivo studies revealed potent antiproliferative activity in the nanomolar range. Mechanism of action studies indicated that Portimine B, similarly to portimine, induced apoptosis and slowed down cancer cell proliferation. Future studies will further explore the antiproliferative effects of this class of compounds.
■
DISCOVERY OF A NOVEL RXR AGONIST WITH IMPROVED IN VITRO PHARMACOKINETIC PROPERTIES Retinoid X receptors (RXR) are nuclear receptors that act as transcription factors. Currently, only two RXR ligands are approved for the treatment of certain cancers, but the unfavorable properties of existing ligands limit their application. In this issue, Heitel et al. (DOI: 10.1021/acsmedchemlett.8b00551) disclose their work that focuses on identifying novel potent RXR agonists. The authors developed a computational model and performed a virtual screen on a commercially available fatty acid mimetic library. The 15 most different chemical entities were selected for a primary in vitro screening against σ, β, and γ RXR, which resulted in the discovery of two novel hits characterized by micromolar activities. Docking analyses of their binding modes led to further optimization studies that yielded derivatives with © 2019 American Chemical Society
pubs.acs.org/acsmedchemlett
Published: February 14, 2019 142
DOI: 10.1021/acsmedchemlett.9b00033 ACS Med. Chem. Lett. 2019, 10, 142−142
