scholarly journals Screening and Identification of Lujo Virus Entry Inhibitors From an Food and Drug Administration-Approved Drugs Library

2021 ◽  
Vol 12 ◽  
Author(s):  
Junyuan Cao ◽  
Siqi Dong ◽  
Yang Liu ◽  
Minmin Zhou ◽  
Jiao Guo ◽  
...  
Keyword(s):  
Drug Administration ◽  
High Throughput Screening ◽  
Food And Drug Administration ◽  
Critical Role ◽  
Lymphocytic Choriomeningitis ◽  
Channel Blockers ◽  
Entry Inhibitors ◽  
Tm Domain ◽  
Virus Entry Inhibitors ◽  
Approved Drugs

Lujo virus (LUJV) belongs to the Old World (OW) genus Mammarenavirus (family Arenaviridae). It is categorized as a biosafety level (BSL) 4 agent. Currently, there are no U.S. Food and Drug Administration (FDA)-approved drugs or vaccines specifically for LUJV or other pathogenic OW mammarenaviruses. Here, a high-throughput screening of an FDA-approved drug library was conducted using pseudotype viruses bearing LUJV envelope glycoprotein (GPC) to identify inhibitors of LUJV entry. Three hit compounds, trametinib, manidipine, and lercanidipine, were identified as LUJV entry inhibitors in the micromolar range. Mechanistic studies revealed that trametinib inhibited LUJV GPC-mediated membrane fusion by targeting C410 [located in the transmembrane (TM) domain], while manidipine and lercanidipine inhibited LUJV entry by acting as calcium channel blockers. Meanwhile, all three hits extended their antiviral spectra to the entry of other pathogenic mammarenaviruses. Furthermore, all three could inhibit the authentic prototype mammarenavirus, lymphocytic choriomeningitis virus (LCMV), and could prevent infection at the micromolar level. This study shows that trametinib, manidipine, and lercanidipine are candidates for LUJV therapy and highlights the critical role of calcium in LUJV infection. The presented findings reinforce the notion that the key residue(s) located in the TM domain of GPC provide an entry-targeted platform for designing mammarenavirus inhibitors.

scholarly journals Screening and Identification of Lujo Virus Entry Inhibitors from an FDA-Approved Drugs Library

2021 ◽  
Author(s):  
Junyuan Cao ◽  
Yang Liu ◽  
Siqi Dong ◽  
Minmin Zhou ◽  
Jiao Guo ◽  
...  
Keyword(s):  
High Throughput Screening ◽  
Critical Role ◽  
Lymphocytic Choriomeningitis ◽  
Channel Blockers ◽  
Entry Inhibitors ◽  
Screening And Identification ◽  
Tm Domain ◽  
Virus Entry Inhibitors ◽  
Approved Drugs ◽  
Fda Approved Drugs

The Lujo virus (LUJV) belongs to the Old World (OW) genus Mammarenavirus (family Arenaviridae); it is categorized as a biosafety level (BSL) 4 agent. Currently, there are no U.S. Food and Drug Administration (FDA)-approved drugs or vaccines specifically for LUJV or other pathogenic OW mammarenaviruses. Here, a high-throughput screening of an FDA-approved drug library was conducted using pseudotype viruses bearing LUJV envelope glycoprotein (GPC) to identify inhibitors of LUJV entry. Three hit compounds, trametinib, manidipine, and lercanidipine, were identified as LUJV entry inhibitors in the micromolar range. Mechanistic studies revealed that trametinib inhibited LUJV GPC-mediated membrane fusion by targeting C410 (located in the transmembrane (TM) domain), while manidipine and lercanidipine inhibited LUJV entry by acting as calcium channel blockers. Meanwhile, all three hits extended their antiviral spectra to the entry of other pathogenic mammarenaviruses. Furthermore, all three could inhibit the authentic prototype mammarenavirus, lymphocytic choriomeningitis virus (LCMV), and could prevent infection at the micromolar level. This study shows that trametinib, manidipine, and lercanidipine are candidates for LUJV therapy, and highlights the critical role of calcium in LUJV infection. The presented findings reinforce the notion that the key residue(s) located in the TM domain of GPC provide an entry-targeted platform for designing mammarenavirus inhibitors.

scholarly journals Screening of FDA-approved Drugs and Identification of Novel Lassa Virus Entry Inhibitors

2018 ◽  
Author(s):  
Peilin Wang ◽  
Yang Liu ◽  
Guangshun Zhang ◽  
Shaobo Wang ◽  
Jiao Guo ◽  
...  
Keyword(s):  
High Throughput Screening ◽  
Transmembrane Domain ◽  
Hemorrhagic Fever ◽  
Mechanistic Study ◽  
Lassa Virus ◽  
Entry Inhibitors ◽  
Glycoprotein Complex ◽  
Virus Entry Inhibitors ◽  
Approved Drugs ◽  
Fda Approved Drugs

ABSTRACTLassa virus (LASV) belongs to the Mammarenavirus genus (family Arenaviridae) and causes severe hemorrhagic fever in humans. At present, there are no Food and Drug Administration (FDA)-approved drugs or vaccines specific for LASV. Herein, high-throughput screening of an FDA-approved drug library was performed against LASV entry using a pseudo-type virus enveloping LASV glycoproteins. Two hit drugs, lacidipine and phenothrin, were identified as LASV entry inhibitors in the micromolar range. A mechanistic study revealed that both drugs inhibited LASV entry by blocking low-pH-induced membrane fusion. Moreover, lacidipine irreversibly bound to the LASV glycoprotein complex (GPC), resulting in virucidal activity. Adaptive mutant analyses demonstrated that replacement of T40, located in the ectodomain of the stable-signal peptide (SSP), with lysine (K) conferred LASV resistance to lacidipine without apparent loss of the viral growth profile. Furthermore, lacidipine showed antiviral activity and specificity against both LASV and the Guanarito virus (GTOV), which is also a category A new world arenavirus. Drug-resistant variants indicate that the V36M in ectodomain of SSP mutant and V436A in the transmembrane domain of GP2 mutant conferred GTOV resistance to lacidipine, suggesting that lacidipine might act via a novel mechanism other than calcium inhibition. This study shows that both lacidipine and phenothrin are candidates for LASV therapy, and the membrane-proximal external region of the GPC might provide an entry-targeted platform for inhibitors.

scholarly journals Screening and Identification of Marburg Virus Entry Inhibitors Using Approved Drugs

2019 ◽  
Vol 35 (2) ◽  
pp. 235-239
Author(s):  
Li Zhang ◽  
Shan Lei ◽  
Hui Xie ◽  
Qianqian Li ◽  
Shuo Liu ◽  
...  
Keyword(s):  
Virus Entry ◽  
Marburg Virus ◽  
Entry Inhibitors ◽  
Screening And Identification ◽  
Virus Entry Inhibitors ◽  
Approved Drugs

scholarly journals Small-Molecule Screens: A Gateway to Cancer Therapeutic Agents with Case Studies of Food and Drug Administration–Approved Drugs

2017 ◽  
Vol 69 (4) ◽  
pp. 479-496 ◽  
Author(s):  
Nathan P. Coussens ◽  
John C. Braisted ◽  
Tyler Peryea ◽  
G. Sitta Sittampalam ◽  
Anton Simeonov ◽  
...  
Keyword(s):  
Case Studies ◽  
Drug Administration ◽  
Small Molecule ◽  
Food And Drug Administration ◽  
Therapeutic Agents ◽  
Approved Drugs

scholarly journals Screening of Botanical Drugs against Lassa Virus Entry

2021 ◽  
Author(s):  
Yang Liu ◽  
Jiao Guo ◽  
Junyuan Cao ◽  
Guangshun Zhang ◽  
Xiaoying Jia ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
High Throughput Screening ◽  
Transmembrane Domain ◽  
Lassa Fever ◽  
Lymphocytic Choriomeningitis ◽  
Mechanistic Study ◽  
Lassa Virus ◽  
Potential Candidate ◽  
Botanical Drug ◽  
Approved Drugs

Lassa virus (LASV) belongs to the Old World Mammarenavirus genus (family Arenaviridae). At present, there are no approved drugs or vaccines specific for LASV. In this study, high-throughput screening of a botanical drug library was performed against LASV entry using a pseudotype virus bearing the LASV envelope glycoprotein complex (GPC). Two hit compounds, bergamottin and casticin, were identified as micromolar range inhibitors of LASV entry. A mechanistic study revealed that casticin inhibited LASV entry by blocking low pH-induced membrane fusion. Analysis of adaptive mutants demonstrated that the F446L mutation, located in the transmembrane domain of GP2, conferred resistance to casticin. Furthermore, casticin antiviral activity extends to the New World (NW) pathogenic mammarenaviruses, and mutation of the conserved F446 also conferred resistance to casticin in these viruses. Unlike casticin, bergamottin showed little effect on LASV GPC-mediated membrane fusion, instead inhibiting LASV entry by blocking endocytic trafficking. Notably, both compounds showed inhibitory effects on authentic lymphocytic choriomeningitis virus. Our study shows that both casticin and bergamottin are candidates for LASV therapy and that the conserved F446 in LASV GPC is important in drug resistance in mammarenaviruses. IMPORTANCE: Currently, there is no approved therapy to treat Lassa fever (LASF). Our goal was to identify potential candidate molecules for LASF therapy. Herein, we screened a botanical drug library and identified two compounds, casticin and bergamottin, that inhibited LASV entry via different mechanisms.

Unapproved Uses of Approved Drugs: The Physician, the Package Insert, and the Food and Drug Administration: Subject Review

PEDIATRICS ◽  
1996 ◽  
Vol 98 (1) ◽  
pp. 143-145 ◽  
Author(s):  
Keyword(s):  
Drug Administration ◽  
Food And Drug Administration ◽  
Age Groups ◽  
Package Insert ◽  
Age Group ◽  
Off Label Use ◽  
Off Label ◽  
Fda Approval ◽  
Approved Drugs

Physicians who prescribe a new drug that has not been approved for a specific indication or a specific age group frequently find themselves in a quandary. Physicians who prescribe "old," time-honored drugs usually do not consult the package insert or search for US Food and Drug Administration (FDA) approval. This statement was written to clarify the legal and informational status of the package insert and the role of the FDA in approving or not approving drugs for specific indications or specific age groups. The unapproved use of approved drugs, or so-called "off-label" use, is extremely prevalent among physicians who care for children. It is important that such use of compounds be brought up to date with current FDA policies and to emphasize the responsibility of the prescribing physician in the use of these compounds.

Report of the Council on Scientific Affairs: Unlabeled Indications of Food and Drug Administration-Approved Drugs

1998 ◽  
Vol 32 (4) ◽  
pp. 1049-1061 ◽  
Author(s):  
Joseph W. Cranston ◽  
Michael A. Williams ◽  
Nancy H. Nielsen ◽  
Rebecca J. Bezman
Keyword(s):  
Drug Administration ◽  
Food And Drug Administration ◽  
Approved Drugs
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