LHF-535(LHF-535) - 药物靶点：Envelope (E) protein_在研适应症：拉沙热_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

Envelope (E) protein

作用机制

包膜（E）蛋白抑制剂

治疗领域

感染其他疾病

在研适应症

拉沙热

非在研适应症-

原研机构

Kineta SA

在研机构

National Institutes of Health

Kineta, Inc. (Washington)Kineta SA

+ [1]

非在研机构

Kineta, Inc.

最高研发阶段临床1期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构

分子式C27H28N2O2

InChIKeyDBNZTRPIBJSUIX-WAYWQWQTSA-N

CAS号1450929-77-7

关联

2

项与 LHF-535 相关的临床试验

NCT03993704 / Completed临床1期

A Double-blind, Placebo-controlled, Dose-escalation Study of the Safety, Tolerability, and Pharmacokinetics of Multiple Oral Doses of LHF-535 (LHF-535-SDD) in Healthy Participants

The purpose of this study is to assess the safety, tolerability, and pharmacokinetics of a daily oral dose of LHF-535 administered for 14 days to healthy participants.

开始日期2019-09-16

申办/合作机构

Kineta, Inc.

[+1]

ACTRN12618001342202 / Completed临床1期

A double-bind, placebo-controlled, dose escalation study of the safety, tolerability, and pharmacokinetics of an oral dose of LHF-535 (LHF-535-SDD) in healthy subjects.

开始日期2018-08-07

申办/合作机构

Clinical Network Services Pty Ltd.

100 项与 LHF-535 相关的临床结果

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100 项与 LHF-535 相关的转化医学

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100 项与 LHF-535 相关的专利（医药）

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4

项与 LHF-535 相关的文献（医药）

2024-09-01·Antiviral Research

Coadministration of LHF-535 and favipiravir protects against experimental Junín virus infection and disease

Article

作者: Amberg, Sean M ; Boardman, Kirsten M ; Bailey, Kevin W ; Westover, Jonna B ; Lustig, Kurt H ; Gowen, Brian B ; Wasson, Samantha R

Argentine hemorrhagic fever, caused by Junín virus (JUNV), is the most common of the South American arenaviral hemorrhagic fevers. The disease has a case fatality rate of 15-30% in untreated patients. Although early intervention with immune plasma is effective, diminishing stocks and limited availability outside of Argentina underscores the need for new therapeutics. Ideally, these would be broadly active agents effective against all the pathogenic arenaviruses. The fusion inhibitor LHF-535 and the nucleoside analog favipiravir have shown promise in animal models of Lassa fever, a disease endemic in parts of Africa and the most prominent of the arenaviral hemorrhagic fevers. Against JUNV, a high dose of favipiravir is required to achieve protection in the gold-standard guinea pig infection model. Here, we demonstrate a synergistic effect by the coadministration of LHF-535 with a sub-optimal dose of favipiravir in guinea pigs challenged with JUNV. Administered individually, LHF-535 and sub-optimal favipiravir only delayed the onset of severe disease. However, combined dosing of the drugs afforded complete protection against lethal JUNV infection in guinea pigs. The benefits of the drug combination were also evident by the absence of viremia and infectious virus in tissues compared to guinea pigs treated with only the placebos. Thus, combined targeting of JUNV-endosomal membrane fusion and the viral polymerase with pan-arenaviral LHF-535 and favipiravir may expand their indication beyond Lassa fever, providing a significant barrier to drug resistance.

2022-11-15·Antimicrobial Agents and Chemotherapy

Safety and Pharmacokinetics of LHF-535, a Potential Treatment for Lassa Fever, in Healthy Adults

Article

作者: Snyder, Benjamin ; Posakony, Jeff ; Heald, Alison E. ; Bedard, Kristin M. ; Amberg, Sean M. ; Vliet-Gregg, Portia A. ; Tarcha, Eric J.

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.

PLOS Pathogens1区 · 医学

A potent Lassa virus antiviral targets an arenavirus virulence determinant

1区 · 医学

ArticleOA

作者: Moore, Amy L ; Madu, Ikenna G ; Tyavanagimatt, Shanthakumar R ; Gharaibeh, Dima N ; Iadonato, Shawn P ; Gowen, Brian B ; Jung, Kie-Hoon ; Jones, Kevin F ; Burgeson, James R ; Bedard, Kristin M ; Korth, Marcus J ; Amberg, Sean M ; Dai, Dongcheng ; Files, Megan

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.

100 项与 LHF-535 相关的药物交易

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