Lassa antiviral LHF-535 protects guinea pigs from lethal challenge

Cashman, Kathleen A.; Wilkinson, Eric R.; Posakony, Jeffrey J.; Madu, Ikenna G.; Tarcha, Eric J.; Lustig, Kurt; Korth, Marcus J.; Bedard, Kristin; Amberg, Sean M.

doi:10.1038/s41598-022-23760-2

Cited by 7 publications

(8 citation statements)

References 29 publications

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“…Its lack of activity against the lineage I strain of LASV and Candid#1 vaccine strain of JUNV mapped to a single amino acid in the GP2 subunit transmembrane region, similar to that seen for the 16G8 analogs ( Plewe et al, 2019 ). However, LHF-535 protected guinea pigs against a lethal dose of lineage IV strain of LASV; intraperitoneal injection of 50 mg/kg daily resulted in 100% survival of animals and undetectable virus at day 35 post-infection, whereas all control animals died by around day 16 ( Cashman et al, 2022 ). The inhibitor also protected mice from a lethal dose of TCRV; an oral dose of 10 mg/kg or 30 mg/kg per day decreased viral titers by 4 logs ( Madu et al, 2018 ).…”

Section: Small Molecule Inhibitors Of Fusionmentioning

confidence: 99%

“…These inhibitors not only demonstrate potent activity against various arenaviruses but also offer insights into the complex mechanisms involved in viral fusion, providing avenues for further research and drug discovery in the fight against these pathogenic viruses. Further, the small molecules first discovered in 2006 led to the development of drugs like ST-193 and LHF-535 that were not toxic at concentrations exhibiting anti-viral activity and which were tested in animal models and even clinical trials in 2021 and 2022 ( Cashman et al, 2011 , 2022 ; Madu et al, 2018 ; Westover et al, 2022 ). The success of these studies demonstrates the potential of these classes of inhibitors.…”

Section: Small Molecule Inhibitors Of Fusionmentioning

confidence: 99%

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Entry inhibitors as arenavirus antivirals

Iyer,

Yan,

Ross

2024

Front. Microbiol.

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Arenaviruses belonging to the Arenaviridae family, genus mammarenavirus, are enveloped, single-stranded RNA viruses primarily found in rodent species, that cause severe hemorrhagic fever in humans. With high mortality rates and limited treatment options, the search for effective antivirals is imperative. Current treatments, notably ribavirin and other nucleoside inhibitors, are only partially effective and have significant side effects. The high lethality and lack of treatment, coupled with the absence of vaccines for all but Junín virus, has led to the classification of these viruses as Category A pathogens by the Centers for Disease Control (CDC). This review focuses on entry inhibitors as potential therapeutics against mammarenaviruses, which include both New World and Old World arenaviruses. Various entry inhibition strategies, including small molecule inhibitors and neutralizing antibodies, have been explored through high throughput screening, genome-wide studies, and drug repurposing. Notable progress has been made in identifying molecules that target receptor binding, internalization, or fusion steps. Despite promising preclinical results, the translation of entry inhibitors to approved human therapeutics has faced challenges. Many have only been tested in in vitro or animal models, and a number of candidates showed efficacy only against specific arenaviruses, limiting their broader applicability. The widespread existence of arenaviruses in various rodent species and their potential for their zoonotic transmission also underscores the need for rapid development and deployment of successful pan-arenavirus therapeutics. The diverse pool of candidate molecules in the pipeline provides hope for the eventual discovery of a broadly effective arenavirus antiviral.

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Section: Small Molecule Inhibitors Of Fusionmentioning

confidence: 99%

Section: Small Molecule Inhibitors Of Fusionmentioning

confidence: 99%

Entry inhibitors as arenavirus antivirals

Iyer,

Yan,

Ross

2024

Front. Microbiol.

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“…According to the Centers for Disease Control and Prevention (CDC), LASV is considered a Category A pathogen due to its high mortality rates and limited therapeutic options [ 7 ]. The World Health Organization (WHO) has made the disease the top priority of research and development [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…GPC is first synthesized as a single polypeptide and then cleaved by signal peptidase and subtilisin/kexin-isoenzyme-1/site-1 proteases (SKI-1/S1P) into three segments: the receptor-binding subunit GP1, the membrane fusion subunit GP2, and the stable signal peptide (SSP) [ 9 , 10 ]. Following the interaction of GP1 with the cellular receptor α-cystine (α-DG) and lysosome-associated membrane protein 1 (LAMP1), viral endocytosis occurs, and GP2 is subjected to a pH-dependent conformational rearrangement, prompting the fusion of viral and endosomal membranes [ 8 , 9 , 11 , 12 , 13 ]. By interacting with GP2 subunits, SSP promotes GPC-mediated membrane fusion at pH and promotes GPC maturation [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

“…Benzimidazole derivatives are special lead compounds for antiviral drugs, attracting interest from many chemists [ 18 , 36 , 37 , 38 , 39 ]. LHF−535 and ST−193 , derivatives of benzimidazoles, are being investigated as promising anti-LASV entry inhibitors ( Figure 1 ) [ 8 , 40 ]. As a small-molecule compound targeting the GPC of LASV, LHF−535 has broad-spectrum activity against different lineages of LASV and related arenaviruses causing HF disease in South America [ 39 ].…”

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis, and Biological Evaluation of Benzimidazole Derivatives as Potential Lassa Virus Inhibitors

Chen

Wang

et al. 2023

Molecules

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The Lassa virus (LASV) causes Lassa fever, a highly infectious and lethal agent of acute viral hemorrhagic fever. At present, there are still no effective treatments available, creating an urgent need to develop novel therapeutics. Some benzimidazole compounds targeting the arenavirus envelope glycoprotein complex (GPC) are promising inhibitors of LASV. In this study, we synthesized two series of LASV inhibitors based on the benzimidazole structure. Lentiviral pseudotypes bearing the LASV GPC were established to identify virus entry inhibitors. Surface plasmon resonance (SPR) was further used to verify the binding activities of the potential compounds. Compounds 7d−Z, 7h−Z, 13c, 13d, and 13f showed relatively excellent antiviral activities with IC50 values ranging from 7.58 to 15.46 nM and their SI values above 1251. These five representative compounds exhibited stronger binding affinity with low equilibrium dissociation constants (KD < 8.25 × 10−7 M) in SPR study. The compound 7h−Z displayed the most potent antiviral activity (IC50 = 7.58 nM) with a relatively high SI value (2496), which could be further studied as a lead compound. The structure–activity relationship indicated that the compounds with lipophilic and spatially larger substituents might possess higher antiviral activity and a much larger safety margin. This study will provide some good guidance for the development of highly active compounds with a novel skeleton against LASV.

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