LHF-535
目录号 : GC65001
LHF-535 是一种抗病毒剂，对 Lassa，Machupo，Junin，VSVg 病毒的 EC50 分别为 <1 μM，<1 μM，<1 μM 和 1-10 μM，详细信息请参考专利文献 WO2012006552A1 中的化合物 1。
Cas No.:1450929-77-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
LHF-535 is an antiviral agent extracted from patent WO2013123215A2, Compound 38, has EC50s of <1 μM, <1 μM, <1 μM, and 1-10 μM for Lassa, Machupo, Junin, and VSVg virus, respectively[1].
LHF-535 is a small-molecule viral entry inhibitor that targets the arenavirus envelope glycoprotein (GP). LHF-535 exhibits potent antiviral activity against a broad array of hemorrhagic fever arenaviruses. LHF-535 inhibits Lassa GP-pseudotyped lentivirus with an IC50 of 0.1-0.3 nM[2].
LHF-535 (3, 10 or 30 mg/kg; orally; daily; 14 days) protectes mice from a lethal challenge with Tacaribe virus and dramatically reduces viral titers in plasma, spleen, and liver[2]. An increase in survival is also observed when the first dose of LHF-535 (10 mg/kg) is delayed by 1, 2, or 3 days after infection, demonstrating that LHF-535 is efficacious as a post-exposure therapeutic in mice[2].
[1]. Dongcheng Dai, et al. Antiviral drugs for treatment of arenavirus infection. WO2013123215A2.
[2]. Madu IG, et al. A potent Lassa virus antiviral targets an arenavirus virulence determinant. PLoS Pathog. 2018 Dec 21;14(12):e1007439.
| Cas No. | 1450929-77-7 | SDF | Download SDF |
| 分子式 | C27H28N2O2 | 分子量 | 412.52 |
| 溶解度 | DMSO : 96.67 mg/mL (234.34 mM; Need ultrasonic) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.4241 mL | 12.1206 mL | 24.2412 mL |
| 5 mM | 0.4848 mL | 2.4241 mL | 4.8482 mL |
| 10 mM | 0.2424 mL | 1.2121 mL | 2.4241 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Lassa antiviral LHF-535 protects guinea pigs from lethal challenge
Sci Rep 2022 Nov 19;12(1):19911.PMID:36402782DOI:10.1038/s41598-022-23760-2.
LHF-535 is a small molecule antiviral currently in development for the treatment of Lassa fever, a zoonotic disease endemic in West Africa that generates significant morbidity and mortality. Current treatment options are inadequate, and there are no approved therapeutics or vaccines for Lassa fever. LHF-535 was evaluated in a lethal guinea pig model of Lassa pathogenesis, using once-daily administration of a fixed dose (50 mg/kg/day) initiating either 1 or 3 days after inoculation with a lethal dose of Lassa virus. LHF-535 reduced viremia and clinical signs and protected all animals from lethality. A subset of surviving animals was rechallenged four months later with a second lethal challenge of Lassa virus and were found to be protected from disease. LHF-535 pharmacokinetics at the protective dose in guinea pigs showed plasma concentrations well within the range observed in clinical trials in healthy volunteers, supporting the continued development of LHF-535 as a Lassa therapeutic.
Safety and Pharmacokinetics of LHF-535, a Potential Treatment for Lassa Fever, in Healthy Adults
Antimicrob Agents Chemother 2022 Nov 15;66(11):e0095122.PMID:36314868DOI:10.1128/aac.00951-22.
LHF-535 is a small-molecule antiviral currently under development as a therapeutic option to treat Lassa fever and other viral hemorrhagic fevers of arenavirus origin. The human safety and pharmacokinetics of LHF-535 were evaluated in two phase 1 trials in healthy volunteers. The first study was a double-blind, single ascending dose trial that evaluated weight-based oral doses ranging from 0.3 mg/kg in the first cohort to 40 mg/kg in the last cohort. The second study was a double-blind, multiple ascending dose trial that evaluated a 14-day oral dosing regimen, with three sequential cohorts receiving fixed doses of 450, 900, or 1,125 mg per day; the third cohort (1,125 mg/day) received a higher (loading) dose of 2,250 mg for the first dose. Each cohort in both studies consisted of eight participants randomized to either placebo (n = 2) or LHF-535 (n = 6). LHF-535 was well tolerated in both studies. Treatment-emergent adverse events were more frequent in placebo recipients than in LHF-535 recipients in both studies. LHF-535 exhibited rapid absorption, a long half-life, and exposures predicted to suppress viral replication.
A potent Lassa virus antiviral targets an arenavirus virulence determinant
PLoS Pathog 2018 Dec 21;14(12):e1007439.PMID:30576397DOI:10.1371/journal.ppat.1007439.
Arenaviruses are a significant cause of hemorrhagic fever, an often-fatal disease for which there is no approved antiviral therapy. Lassa fever in particular generates high morbidity and mortality in West Africa, where the disease is endemic, and a recent outbreak in Nigeria was larger and more geographically diverse than usual. We are developing LHF-535, a small-molecule viral entry inhibitor that targets the arenavirus envelope glycoprotein, as a therapeutic candidate for Lassa fever and other hemorrhagic fevers of arenavirus origin. Using a lentiviral pseudotype infectivity assay, we determined that LHF-535 had sub-nanomolar potency against the viral envelope glycoproteins from all Lassa virus lineages, with the exception of the glycoprotein from the LP strain from lineage I, which was 100-fold less sensitive than that of other strains. This reduced sensitivity was mediated by a unique amino acid substitution, V434I, in the transmembrane domain of the envelope glycoprotein GP2 subunit. This position corresponds to the attenuation determinant of Candid#1, a live-attenuated Junín virus vaccine strain used to prevent Argentine hemorrhagic fever. Using a virus-yield reduction assay, we determined that LHF-535 potently inhibited Junín virus, but not Candid#1, and the Candid#1 attenuation determinant, F427I, regulated this difference in sensitivity. We also demonstrated that a daily oral dose of LHF-535 at 10 mg/kg protected mice from a lethal dose of Tacaribe virus. Serial passage of Tacaribe virus in LHF-535-treated Vero cells yielded viruses that were resistant to LHF-535, and the majority of drug-resistant viruses exhibited attenuated pathogenesis. These findings provide a framework for the clinical development of LHF-535 as a broad-spectrum inhibitor of arenavirus entry and provide an important context for monitoring the emergence of drug-resistant viruses.