Cell-Free Protein Synthesizing Systems As Tools for Discovery of Drugs Inhibiting Viral Capsid Assembly

Lingappa, Vishwanath R.; Harrell, Emma; Copeland, Kiel; Prasad, M. Dharma; Asundi, Vinod K.; Hahner, Nick; Francis, Jean; Dey, Debendranath; Welsh, Jennifer; Macieik, Amanda; Lingappa, Jaisri R.; Kelleher, CC; Hurt, Clarence R.; Hansen, Wendy F.

doi:10.1016/j.antiviral.2010.02.453

Cited by 2 publications

(1 citation statement)

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“…From a cell-free capsid assembly assay screen of a chemical library (Lingappa et al, 2010;Lingappa et al, 2013b) similar to what we have successfully described for rabies virus (Lingappa et al, 2013a), human immunodeficiency virus (HIV) (Reed et al, 2021), and respiratory viruses (Selvarajah et al, 2021), an early lead compound (1.32) was identified with activity in inhibiting herpes virus capsid assembly. This compound was subsequently optimized for activity over seven generations to lead to an improved compound 7.25 that inhibited HSV-1 replication in a dose-dependent manner in HSV-1-infected Vero cells both in a standard plaque assay (Figure 1A) and in an in-cell ELISA (Figure 1B) with an EC 50 of 32 nM or 25 nM, respectively, and an LD 50 of 1.12 µM (Supplementary Figure 1).…”

Section: Anti-hsv1 Activity Of a Novel Compound Directed To Host Factors Assisting In Hsv1 Assemblymentioning

confidence: 99%

Oxidized MIF is an Alzheimer’s Disease drug target relaying external risk factors to tau pathology

Mueller-Schiffmann

Torres

Kitaygorodskyy³

et al. 2021

Preprint

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Herpes virus infections are endemic and ubiquitous. While only rarely leading to overt encephalitis, subchronic or latent infections have been associated to a variety of conditions, including Alzheimer's disease (AD). The cellular consequences of herpes virus infection are determined by the host proteins recruited during virus replication and assembly. Identifying such virus-recruited host proteins therefore allows the interrogation fundamental cellular events leading to associated "sporadic" diseases. A host protein-targeted small molecule drug highly active against herpes simplex virus 1 (HSV-1) infection in human brain organoids and cell lines was identified to interact with macrophage migration inhibitory factor (MIF) where it acted by intercalating between MIF units within a trimer, as determined by nuclear magnetic resonance (NMR). MIF knockout cells showed a decreased viral antigen/titer ratio corroborating its role in virus assembly. From post-mortem brain homogenates of patients with Braak 6-staged AD the small molecule lead compound specifically eluted a MIF subpopulation that correlated with the oxidized conformer of MIF (oxMIF). HSV-1 led to an increase in tau phosphorylation at distinct residues, and the lead compound decreased tau phosphorylation in recombinant cell lines expressing mutant tau and in neuron-differentiated iPSCs also in the absence of HSV-1 infection. We conclude that MIF is a cellular host factor involved in HSV-1 replication and a drug target with antiviral efficacy. At the same time, MIF also plays a role in tau phosphorylation and is enriched in an oxidized conformation in brains of AD patients. MIF thus presents as a molecular link connecting HSV-1 infection and cellular pathology characteristic of neurodegenerative diseases involving aberrant tau phosphorylation.

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Section: Anti-hsv1 Activity Of a Novel Compound Directed To Host Factors Assisting In Hsv1 Assemblymentioning

confidence: 99%

Oxidized MIF is an Alzheimer’s Disease drug target relaying external risk factors to tau pathology

Mueller-Schiffmann

Torres

Kitaygorodskyy³

et al. 2021

Preprint

Self Cite

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A Pan-Respiratory Antiviral Chemotype Targeting a Host Multi-Protein Complex

Selvarajah¹,

Lingappa²,

Michon³

et al. 2021

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Antiviral compounds displaying remarkable features have been identified by an unconventional drug screen and advanced through animal validation. Efficacy is observed against the six viral families causing most human respiratory viral disease, irrespective of strain, including both influenza (FLUV) and SARS-CoV-2, with cell culture EC50 at or below 100 nM. Survival benefit is demonstrated in pigs against another member of family Coronaviridae, porcine epidemic diarrhea virus (PEDV), and shown equally effective in mild and severe disease. Respiratory syncytial virus (RSV) titer is reduced by drug treatment in cotton rats. A substantial barrier to viral resistance is demonstrated for FLUV. Drug resin affinity chromatography (DRAC) reveals a novel drug target: a multi-protein complex (MPC) formed transiently, in an energy-dependent fashion, and composed of host proteins implicated in both viral lifecycles and manipulation of innate immunity. The protein composition of this host MPC is modified upon viral infection, with increase or decrease of some proteins and appearance or complete loss of others. Valosin-containing protein, also known as Transitional endoplasmatic reticulum ATPase (VCP/p97), is present in the target MPC of uninfected cells and significantly increased in both FLUV and CoV infection. SQSTM1/p62, a key regulator of the autophagy pathway of innate immunity whose dysfunction is implicated in cytokine storm, is i) found in the target MPC from uninfected cells, ii) diminished in DRAC eluates by infection, and iii) restored by drug treatment of infected cells. 14-3-3 is one of likely several proteins that comprise the drug-binding site. Advanced compounds with improved pharmacokinetic (PK) properties and lung exposure are approaching criteria for a Target Product Profile. We propose these novel drug targets to comprise a previously unappreciated molecular basis for homeostasis that is modified by viruses to allow exploitation for viral propagation and is restored by treatment with the therapeutic compounds presented. This discovery has transformative implications for treatment of respiratory viral-related disease, applicable to everything from seasonal FLUV to COVID-19 and future novel respiratory viruses, due to the pan-family nature of drug activity and barrier to resistance development.

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Cell-Free Protein Synthesizing Systems As Tools for Discovery of Drugs Inhibiting Viral Capsid Assembly

Cited by 2 publications

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Oxidized MIF is an Alzheimer’s Disease drug target relaying external risk factors to tau pathology

Oxidized MIF is an Alzheimer’s Disease drug target relaying external risk factors to tau pathology

A Pan-Respiratory Antiviral Chemotype Targeting a Host Multi-Protein Complex

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