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Recently, Frontiers in Microbiology, an international academic journal of microbiology, published the latest research results of Xiao Gengfu and Wang Wei's team at Wuhan Institute of Virology, Chinese Academy of Sciences/Biosafety Science Research Center
.
The paper is entitled "Screening and Identification of Lujo Virus Entry Inhibitors From an Food and Drug Administration-Approved Drugs Library" (screening and identification of Lujo Virus Entry Inhibitors From an Food and Drug Administration-Approved Drugs Library)
.
The team successfully screened inhibitors that block the entry of Lujo virus (LUJV), and further revealed the entry mechanism of LUJV by revealing the mechanism of action of the inhibitor
.
LUJV belongs to the arenaviridae family (Arenaviridae), the mammalian arenavirus genus (Mammarenavirus)
.
LUJV, as a grade four pathogen, can cause severe viral hemorrhagic fever
.
Zambia and South Africa reported 5 cases of LUJV infection in 2008, 4 of which were fatal, and the mortality rate was as high as 80%
.
As there are currently no drugs and vaccines for specific treatment of LUJV infection, there is an urgent need to develop effective and safe drugs for the treatment of LUJV infection
.
The research team used a recombinant virus with vesicular stomatitis virus (VSV) as the backbone and LUJV envelope glycoprotein (GPC) to conduct high-throughput screening of FDA-approved drug libraries
.
After multiple rounds of screening, three drugs targeting LUJV entry, trametinib, manidipine, and lercanidipine were obtained
.
Trametinib inhibits the entry of LUJV by inhibiting LUJV-GPC-mediated membrane fusion
.
By screening the drug-resistant virus strains of trametinib, it was found that the mutation at position 410 of the transmembrane region of LUJV-GP2 from cysteine to glycine can make LUJV obtain drug resistance
.
Trametinib has a broad-spectrum antiviral effect on arenavirus
.
Further studies have found that trametinib can also inhibit the entry of Old World Arenavirus by targeting the F446 site located at the SSP-GP2 interaction interface
.
Manidipine and Lercanidipine are dihydropyridine calcium ion channel inhibitors and show broad-spectrum antiviral effects against New World Arenavirus
.
Knockdown of the calcium channel protein subunit CACNA1S will reduce the infection of LUJV, suggesting that these two inhibitors inhibit the entry of LUJV by targeting calcium channels
.
The study found candidate drugs for the treatment of LUJV infection, revealed the role of calcium ion channels in LUJV infection, and emphasized the key role of key amino acids located in the transmembrane region of GPC in the process of LUJV infection, providing for the development of antiviral drugs An important reference
.
.
Doctoral student Cao Junyuan of Wuhan Institute of Virology, master student Siqi Dong and experimenter Liu Yang are the co-first authors of the paper, and researcher Xiao Gengfu and associate researcher Wang Wei are the co-corresponding authors of the paper
.
This work was supported by the National Key Research and Development Program (2018YFA0507204), the National Natural Science Foundation of China (82172273, 31670165), the High-end User Cultivation Project of the Wuhan National Biosafety Laboratory of the Chinese Academy of Sciences (2019ACCP-MS03), and the Open Research Fund Project of the State Key Laboratory of Virology (2018IOV001) ) Funding
.
Figure 1: Screening and identification of LUJV invasion inhibitors
Article link:
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