Targeting SARS-CoV-2 entry processes: The promising potential and future of host-targeted small-molecule inhibitors

Wu, Aijia; Shi, Kunyu; Wang, Jiaxing; Zhang, Ruofei; Wang, Yuxi

doi:10.1016/j.ejmech.2023.115923

Cited by 11 publications

(4 citation statements)

References 153 publications

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“…Given the range metabolic effects resulting from inhibition of PIKFYVE, selectively terminating autophagy-dependent cancers is only one therapeutic target for PIKFYVE inhibitors. Clinical trials of published PIKFYVE inhibitors are underway in the treatment of SARS-CoV-2 and other RNA virus infections [121], as well as amyotrophic lateral sclerosis (ALS) [112,122] and other neurological diseases [41]. Trials are also underway for the proprietary PIKFYVE inhibitor from Verge Genomics (VRG50635) against ALS.…”

Section: Discussionmentioning

confidence: 99%

Selective Termination of Autophagy-Dependent Cancers

Roy,

DePamphilis

2024

Cells

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The goal of cancer research is to identify characteristics of cancer cells that allow them to be selectively eliminated without harming the host. One such characteristic is autophagy dependence. Cancer cells survive, proliferate, and metastasize under conditions where normal cells do not. Thus, the requirement in cancer cells for more energy and macromolecular biosynthesis can evolve into a dependence on autophagy for recycling cellular components. Recent studies have revealed that autophagy, as well as different forms of cellular trafficking, is regulated by five phosphoinositides associated with eukaryotic cellular membranes and that the enzymes that synthesize them are prime targets for cancer therapy. For example, PIKFYVE inhibitors rapidly disrupt lysosome homeostasis and suppress proliferation in all cells. However, these inhibitors selectively terminate PIKFYVE-dependent cancer cells and cancer stem cells with not having adverse effect on normal cells. Here, we describe the biochemical distinctions between PIKFYVE-sensitive and -insensitive cells, categorize PIKFYVE inhibitors into four groups that differ in chemical structure, target specificity and efficacy on cancer cells and normal cells, identify the mechanisms by which they selectively terminate autophagy-dependent cancer cells, note their paradoxical effects in cancer immunotherapy, and describe their therapeutic applications against cancers.

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Section: Discussionmentioning

confidence: 99%

Selective Termination of Autophagy-Dependent Cancers

Roy,

DePamphilis

2024

Cells

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“…However, entry inhibitor activity may or may not necessarily be related to previously known "host-dependent" mechanisms of action. While numerous viral entry inhibitors have been identified that target a host protein and exhibit "host-dependent" mechanisms of action, we do not aim to summarize those that have been recently reviewed elsewhere [41,42]. Rather, we aim to focus on small molecules that act by binding directly to the Spike protein with various "Spike-dependent" mechanisms of action.…”

Section: Small Molecule Entry Inhibitors Of Sars-cov-2 Spikementioning

confidence: 99%

Research Progress on Spike-Dependent SARS-CoV-2 Fusion Inhibitors and Small Molecules Targeting the S2 Subunit of Spike

Freidel,

Armen

2024

Viruses

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Since the beginning of the COVID-19 pandemic, extensive drug repurposing efforts have sought to identify small-molecule antivirals with various mechanisms of action. Here, we aim to review research progress on small-molecule viral entry and fusion inhibitors that directly bind to the SARS-CoV-2 Spike protein. Early in the pandemic, numerous small molecules were identified in drug repurposing screens and reported to be effective in in vitro SARS-CoV-2 viral entry or fusion inhibitors. However, given minimal experimental information regarding the exact location of small-molecule binding sites on Spike, it was unclear what the specific mechanism of action was or where the exact binding sites were on Spike for some inhibitor candidates. The work of countless researchers has yielded great progress, with the identification of many viral entry inhibitors that target elements on the S1 receptor-binding domain (RBD) or N-terminal domain (NTD) and disrupt the S1 receptor-binding function. In this review, we will also focus on highlighting fusion inhibitors that target inhibition of the S2 fusion function, either by disrupting the formation of the postfusion S2 conformation or alternatively by stabilizing structural elements of the prefusion S2 conformation to prevent conformational changes associated with S2 function. We highlight experimentally validated binding sites on the S1/S2 interface and on the S2 subunit. While most substitutions to the Spike protein to date in variants of concern (VOCs) have been localized to the S1 subunit, the S2 subunit sequence is more conserved, with only a few observed substitutions in proximity to S2 binding sites. Several recent small molecules targeting S2 have been shown to have robust activity over recent VOC mutant strains and/or greater broad-spectrum antiviral activity for other more distantly related coronaviruses.

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“…To the best of our knowledge, no drug targeting the spike RBD/ACE2 interaction is currently used in the clinic [92]. While the widely cited chloroquine, hydroxychloroquine, and ivermectin appeared somewhat deceiving in clinical trials, the potential of spike RBD/ACE2 modulators is such [93] that it remains worthwhile to define possibly useful compounds. Ivermectin is included in our tested natural products and can be considered a "reference drug".…”

Section: Tested Natural Productsmentioning

confidence: 99%

Microfluidic Diffusion Sizing Applied to the Study of Natural Products and Extracts That Modulate the SARS-CoV-2 Spike RBD/ACE2 Interaction

Fauquet,

Carette,

Duez

et al. 2023

Molecules

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The interaction between SARS-CoV-2 spike RBD and ACE2 proteins is a crucial step for host cell infection by the virus. Without it, the entire virion entrance mechanism is compromised. The aim of this study was to evaluate the capacity of various natural product classes, including flavonoids, anthraquinones, saponins, ivermectin, chloroquine, and erythromycin, to modulate this interaction. To accomplish this, we applied a recently developed a microfluidic diffusional sizing (MDS) technique that allows us to probe protein-protein interactions via measurements of the hydrodynamic radius (Rh) and dissociation constant (KD); the evolution of Rh is monitored in the presence of increasing concentrations of the partner protein (ACE2); and the KD is determined through a binding curve experimental design. In a second time, with the protein partners present in equimolar amounts, the Rh of the protein complex was measured in the presence of different natural products. Five of the nine natural products/extracts tested were found to modulate the formation of the protein complex. A methanol extract of Chenopodium quinoa Willd bitter seed husks (50 µg/mL; bisdesmoside saponins) and the flavonoid naringenin (1 µM) were particularly effective. This rapid selection of effective modulators will allow us to better understand agents that may prevent SARS-CoV-2 infection.

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Targeting SARS-CoV-2 entry processes: The promising potential and future of host-targeted small-molecule inhibitors

Cited by 11 publications

References 153 publications

Selective Termination of Autophagy-Dependent Cancers

Selective Termination of Autophagy-Dependent Cancers

Research Progress on Spike-Dependent SARS-CoV-2 Fusion Inhibitors and Small Molecules Targeting the S2 Subunit of Spike

Microfluidic Diffusion Sizing Applied to the Study of Natural Products and Extracts That Modulate the SARS-CoV-2 Spike RBD/ACE2 Interaction

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