Flavivirus infection usually results in fever accompanied by headache, arthralgia, and, in some cases, rash. Although the symptoms are mild, full recovery can take several months. Flaviviruses encode seven nonstructural proteins that represent potential drug targets for this viral family. Focusing on the Zika virus NS2B-NS3 protease, we uncovered a unique inhibitor, MH1, composed of aminothiazolopyridine and benzofuran moieties. MH1 inhibits ZVP with a biochemical IC₅₀ of 440 nM and effectively blocks cleavage of ZVP substrates in cells. Surprisingly, MH1 inhibits the other flaviviral proteases at least 18-fold more weakly. This same phenomenon was observed in assays of the viral cytopathic effect, where only Zika virus showed sensitivity to MH1. This selectivity was unexpected since flaviviral proteases have high similarity in sequence and protein structure. MH1 binds at an allosteric site, as demonstrated by its ability to stabilize ZVP synergistically with an active site inhibitor. To understand its selectivity, we constructed a series of hybrid proteases composed of select segments of ZVP, which is sensitive to MH1, and dengue virus protease, which is essentially insensitive to MH1. Our results suggest that MH1 binds to the NS3 protease domain, disrupting its interaction with NS2B. These interactions are essential for substrate binding and cleavage. In particular, the unique dynamic properties of NS2B from Zika seem to be required for the function of MH1. Insights into the mechanism of MH1 function will aid us in developing non-active-site-directed, pan-flaviviral inhibitors, by highlighting the importance of evaluating and considering the dynamics of the NS2B regions.

21 Jun 2018·Genome Announcements

Complete Genome Sequence of Bacillus subtilis Strain MH1, Which Has a High Level of Bacteriocin-Like Activity, Isolated from Soil in Bangladesh

Article

Author: Akhter, Marufa Zerin ; Hossain, Muhammad Maqsud ; Shishir, M. Asaduzzaman ; Khan, Shakila Nargis ; Hossain, Mohammad Shahnoor ; Hoq, M. Mozammel

ABSTRACTBacillus subtilis MH1 demonstrates a high level of bacteriocin activity against several pathogenic bacteria. We announce here the full-genome sequence of strain MH1, isolated from soil in Bangladesh. This genome length is 4,094,053 bp, with 43.5% GC content, 4,217 coding sequences (CDS), 10 rRNA, 84 tRNA, and 1 transfer-messenger RNA (tmRNA).

01 Apr 2015·InflammationQ2 · MEDICINE

Effects of Mouse Hepcidin 1 Treatment on Osteoclast Differentiation and Intracellular Iron Concentration

Q2 · MEDICINE

Article

Author: Guo-yang Zhao ; Dong-hua Di ; Xi Huang ; You-jia Xu ; Bo Wang

Hepcidin is a key player in the regulation of mammalian iron homeostasis. Because iron overload may be one of the causes of osteoporosis, hepcidin may have therapeutic potential for osteoporosis patients. However, the effects of hepcidin on bone metabolism are not fully clear. We recently found that hepcidin can increase intracellular iron and calcium levels and promote mineralization in osteoblasts. The present study was designed to evaluate the effects of hepcidin on osteoclasts. Our results showed that mouse hepcidin 1 (MH1) can increase the number of TRAP-positive MNCs concomitant in both bone marrow-derived macrophages (BMMs) and RAW264.7 cells and upregulate mRNA levels of TRAP, cathepsin K, and MMP-9 and increase TRAP-5b protein secretion in RAW264.7 cells. Moreover, MH1 can downregulate the level of FPN1 protein and increase intracellular iron in RAW 264.7 cells. Therefore, we conclude that MH1 can significantly facilitate osteoclast differentiation in vitro. The mechanism behind accelerated differentiation may be associated with increased levels of intracellular iron. These findings may facilitate understanding of the effects of hepcidin on bone metabolism.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Phase 2	-	QHSLab, Inc.	-

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