A pan-respiratory antiviral chemotype targeting a transient host multi-protein complex

Open Biology, Journal Year: 2024, Volume and Issue: 14(6)

Published: June 1, 2024

We present a novel small molecule antiviral chemotype that was identified by an unconventional cell-free protein synthesis and assembly-based phenotypic screen for modulation of viral capsid assembly. Activity PAV-431, representative compound from the series, has been validated against infectious viruses in multiple cell culture models all six families causing most respiratory diseases humans. In animals, this demonstrated efficacious porcine epidemic diarrhoea virus (a coronavirus) syncytial paramyxovirus). PAV-431 is shown to bind 14-3-3, known allosteric modulator. However, it only appears target subset 14-3-3 which dynamic multi-protein complex whose components include proteins implicated life cycles innate immunity. The composition be modified upon infection largely restored treatment. An advanced analog, PAV-104, selective virally target, thereby avoiding host toxicity. Our findings suggest new paradigm understanding, drugging, host–virus interface, leads clinical therapeutic strategy treatment disease.

Language: Английский

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SARS-CoV-2 Omicron variations reveal mechanisms controlling cell entry dynamics and antibody neutralization

PLoS Pathogens, Journal Year: 2024, Volume and Issue: 20(12), P. e1012757 - e1012757

Published: Dec. 2, 2024

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is adapting to continuous presence in humans. Transitions endemic infection patterns are associated with changes the spike (S) proteins that direct virus-cell entry. These generate antigenic drift and thereby allow virus maintenance face of prevalent human antiviral antibodies. also fine tune entry dynamics ways optimize transmission into cells. Focusing on latter aspect, we evaluated effects several S protein substitutions membrane fusion, an essential final step enveloped Membrane fusion executed by integral-membrane “S2” domains, yet found peripheral “S1” domains altered late-stage dynamics, consistent S1-S2 heterodimers cooperating throughout cell A specific H655Y change S1 stabilized a fusion-intermediate conformation delayed fusion. The sensitized viruses neutralization S2-targeting fusion-inhibitory peptides stem-helix antibodies did not interfere early fusion-activating steps; rather they targeted latest stages S2-directed novel mechanism. findings demonstrate single amino acid both reset viral entry—fusion kinetics increase sensitivity antibody neutralization. results exemplify how selective forces driving SARS-CoV-2 fitness evasion operate together shape evolution.

Language: Английский

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Small molecule protein assembly modulators with pan-cancer therapeutic efficacy

Open Biology, Journal Year: 2024, Volume and Issue: 14(12)

Published: Dec. 1, 2024

Two structurally unrelated small molecule chemotypes, represented by compounds PAV-617 and PAV-951, with antiviral activity in cell culture against Mpox virus (formerly known as monkeypox virus) human immunodeficiency (HIV) respectively, were studied for anti-cancer efficacy. Each exhibited apparent pan-cancer cytotoxicity reasonable pharmacokinetics. Non-toxicity is demonstrated a non-cancer line mice at doses achieving drug exposure active concentrations. Anti-tumour properties of both chemotypes validated mouse xenografts A549 lung cancer and, one the HT-29 colorectal cancer. The targets these are unconventional: each binds to different transient, energy-dependent multi-protein complex. Treatment alters target complexes manner that appears remove block, crucial survival progression, on homeostatic linkage between uncontrolled proliferation apoptosis. These provide starting points development novel, next-generation, non-toxic, therapeutics.

Language: Английский

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SARS-CoV-2 Assembly: Gaining Infectivity and Beyond

Viruses, Journal Year: 2024, Volume and Issue: 16(11), P. 1648 - 1648

Published: Oct. 22, 2024

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was responsible for causing the COVID-19 pandemic. Intensive research has illuminated complex biology of SARS-CoV-2 and its continuous evolution during after While much attention been paid to structure functions viral spike protein entry step infection, partly because these are targets neutralizing antibodies vaccines, later stages replication, including assembly egress progenies, remain poorly characterized. This includes insight into how activities structural proteins orchestrated spatially temporally, which cellular assimilated by virus assist assembly, counters evades mechanisms antagonizing assembly. In addition becoming infectious, progenies also need survive hostile innate adaptive immune mechanisms, such as recognition antibodies. review offers an updated summary roles in regulation factors, that restrict this process. Knowledge key events often reveals vulnerabilities aids development effective antiviral therapeutics.

Language: Английский

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MMPred: a tool to predict peptide mimicry events in MHC class II recognition

Frontiers in Genetics, Journal Year: 2024, Volume and Issue: 15

Published: Dec. 10, 2024

We present MMPred, a software tool that integrates epitope prediction and sequence alignment algorithms to streamline the computational analysis of molecular mimicry events in autoimmune diseases. Starting with two protein or peptide sets (e.g., from human SARS-CoV-2), MMPred facilitates generation, investigation, testing hypotheses by providing predictions specifically for MHC class II alleles, which are frequently implicated autoimmunity. However, is easily extendable I incorporating pre-trained models CNN-PepPred NetMHCpan. To evaluate MMPred's ability produce biologically meaningful insights, we conducted comprehensive assessment involving

Language: Английский

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