DOI： 10.64898/2025.12.25.696505

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

<jats:p>The COVID-19 pandemic made plain the need for effective antivirals acting on novel antiviral targets, among which viral macrodomains have attracted considerable attention. We recently described AVI-4206 (1), a potent and selective inhibitor of the SARS-CoV-2 ADP-ribosylhydrolase Mac1 based on a 9H-pyrimido[4,5-b]indole core, the first Mac1 inhibitor to demonstrate antiviral efficacy in mouse models of SARS-CoV-2 infection, but requiring IP administration and frequent dosing. Herein we describe an extensive, structurally enabled medicinal chemistry effort to identify orally bioavailable Mac1 inhibitors by addressing permeability and efflux liabilities of 1 and many of its analogs. Multiple strategies were pursued to overcome these issues, including replacing a urea function to reduce hydrogen bond donor count. While heterocyclic urea mimetics could deliver analogs like AVI-6318 (3) with potencies and ADME profiles similar to 1, abrogation of the P-gp liability was finally achieved with entirely non-polar substituents in place of urea. Thus, AVI-6451 (4) is a potent Mac1 inhibitor lead with low intrinsic clearance, high oral bioavailability, and antiviral efficacy with once-daily oral administration in a mouse model of SARS-CoV-2 infection</jats:p>

DOI： 10.1021/acs.jmedchem.5c02933

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

<jats:title>Abstract</jats:title>
<jats:p>Bond-selective vibrational imaging techniques, such as Raman spectroscopy, are opening up many applications that were previously considered impossible or inaccessible by other means, such as fluorescence imaging. In particular, vibrational microscopy offers unique advantages, such as the ability to perform highly multiplexed, label-free imaging. Indeed, recent advances in optical and chemical technologies have made it possible to image biological phenomena at the cellular level with high sensitivity, high resolution, and high specificity. Applications of vibrational microscopy both in biological research and in medicine, including the detection of pathological lesions, are expanding rapidly. Here, we provide a general overview of Raman microscopy, and we review recent progress in cutting-edge applications, including label-free imaging and the development of small Raman tags, Raman probes enabling highly sensitive ultra-multiplexed observation, and functional Raman probes.</jats:p>

DOI： 10.1186/s41232-025-00400-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

<jats:title>Abstract</jats:title><jats:p>SARS-CoV-2 continues to pose a threat to public health. Current therapeutics remain limited to direct acting antivirals that lack distinct mechanisms of action and are already showing signs of viral resistance. The virus encodes an ADP-ribosylhydrolase macrodomain (Mac1) that plays an important role in the coronaviral lifecycle by suppressing host innate immune responses. Genetic inactivation of Mac1 abrogates viral replication<jats:italic>in vivo</jats:italic>by potentiating host innate immune responses. However, it is unknown whether this can be achieved by pharmacologic inhibition and can therefore be exploited therapeutically. Here we report a potent and selective lead small molecule, AVI-4206, that is effective in an<jats:italic>in vivo</jats:italic>model of SARS-CoV-2 infection. Cellular models indicate that AVI-4206 has high target engagement and can weakly inhibit viral replication in a gamma interferon- and Mac1 catalytic activity-dependent manner; a stronger antiviral effect for AVI-4206 is observed in human airway organoids. In an animal model of severe SARS-CoV-2 infection, AVI-4206 reduces viral replication, potentiates innate immune responses, and leads to a survival benefit. Our results pharmacologically validate Mac1 as a therapeutic target via a novel immune-restoring mechanism that could potentially synergize with existing therapies targeting distinct, essential aspects of the coronaviral life cycle. This approach could be more widely used to target other viral macrodomains to develop antiviral therapeutics beyond COVID-19.</jats:p>

DOI： 10.7554/elife.103484.3

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掲載種別：研究論文（学術雑誌）  

<jats:title>ABSTRACT</jats:title><jats:p>Small molecule ligands exhibit a diverse range of conformations in solution. Upon binding to a target protein, this conformational diversity is generally reduced. However, ligands can retain some degree of conformational flexibility even when bound to a receptor. In the Protein Data Bank (PDB), a small number of ligands have been modeled with distinct alternative conformations that are supported by X-ray crystallography density maps. However, the vast majority of structural models are fit to a single ligand conformation, potentially ignoring the underlying conformational heterogeneity present in the sample. We previously developed qFit-ligand to sample diverse ligand conformations and to select a parsimonious ensemble consistent with the density. While this approach indicated that many ligands populate alternative conformations, limitations in our sampling procedures often resulted in non-physical conformations and could not model complex ligands like macrocycles. Here, we introduce several improvements to qFit-ligand, including the use of routines within RDKit for stochastic conformational sampling. This new sampling method greatly enriches low energy conformations of small molecules and macrocycles. We further extended qFit-ligand to identify alternative conformations in PanDDA-modified density maps from high throughput X-ray fragment screening experiments. The new version of qFit-ligand improves fit to electron density and reduces torsional strain relative to deposited single conformer models and our previous version of qFit-ligand. These advances enhance the analysis of residual conformational heterogeneity present in ligand-bound structures, which can provide important insights for the rational design of therapeutic agents.</jats:p>

DOI： 10.7554/eLife.103797.3

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出願人：国立研究開発法人産業技術総合研究所, 国立大学法人東京大学

出願番号：特願2026-077541  出願日：2026年5月

権利者：国立研究開発法人産業技術総合研究所

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出願番号：特願2021-173456  出願日：2021年10月

公表番号：WO2023068376A1  公表日：2022年4月

出願国：国内 , 外国   取得国：国内 , 外国

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