Biology subjects

Matsunaga, N.

Publications and source records attributed to Matsunaga, N..

6 recordsLinked to original sources

bioRxiv2026

Structural basis for the intestinal protocadherin-based intermicrovillar adhesion complex

The intestinal brush border (BB), composed of densely packed microvilli on enterocytes, is essential for nutrient absorption and host defense. Its organization relies on the intermicrovillar adhesion complex (IMAC), mediated by protocadherins CDHR2 and CDHR5. Despite their clinical relevance in inflammatory bowel disease and several carcinomas, structural details of IMAC assemblies have remained elusive. Herein, we report the Cryo-EM structure of the adhesive complex at 3.4 [A] resolution, revealing a heterotetrameric ensemble composed of a dimer of CDHR2 and a dimer of CDHR5. This assembly ensures uniform adhesive strength between neighboring microvilli, and facilitates hexagonal packing of microvilli. Biophysical analyses and molecular dynamics simulations revealed a kinked, Ca{superscript 2}-free linker between domains EC3 and EC4 of CDHR5 conferring the necessary flexibility to withstand the shear stress caused during intestinal peristalsis. Collectively, these findings provide a structural framework for understanding BB organization and suggest strategies for therapeutics targeting IMAC in intestinal disorders.

biophysics↗

bioRxiv2026

Small molecule inhibition of the mitochondrial lipid transfer protein STARD7 attenuates influenza viral replication

The increasing appearance of drug-resistant and zoonotic influenza strains highlights an urgent need for host-directed antivirals that offer broad-spectrum activity and a higher barrier to resistance. Here, we describe the characterization of M4, a small-molecule identified from a high-thoughput screen that potently inhibits influenza A and B viruses. Mechanistic studies reveal that M4 suppresses replication by causing nuclear retention of the viral ribonucleoprotein (vRNP) complex. Chemoproteomic profiling identified the lipid transfer protein STARD7 as the primary cellular target, and genetic depletion of STARD7 phenocopies the antiviral effects of M4. Additional studies localizes the M4 binding site to cysteine 302 within the lipid-binding domain of STARD7, supporting a model in which STARD7-dependent lipid transfer activity promotes efficient vRNP trafficking and nuclear export. Combining M4 with baloxavir enhances antiviral efficacy in a murine infection model, providing in vivo support for a host-directed strategy. Together, these results identify STARD7 as a metabolic checkpoint licensing vRNP export and establish a proof of concept for therapeutic intervention with small molecule inhibitors. Author SummaryInfluenza viruses continue to cause widespread illness and pose an ongoing pandemic threat, in part because existing antiviral drugs can lose effectiveness as the virus evolves resistance. To address this challenge, we focused on identifying therapies that target host cell processes required for viral replication, rather than viral proteins themselves. In this study, we describe a small molecule, M4, that inhibits replication of both influenza A and B viruses by blocking a critical step in the viral life cycle. We found that M4 acts on a host protein called STARD7, which helps move certain lipids to the right places inside cells. When STARD7 is inhibited, the influenza viral ribonucleoprotein (vRNP) complex becomes trapped in the cell nucleus and cannot reach the cytoplasm, preventing the virus from completing its replication cycle. Disrupting STARD7 genetically produces the same effect, confirming that this host protein is important for influenza replication. These findings point to a previously unrecognized host gating mechanism that controls nuclear export of the vRNP complex during infection. Although M4 alone showed limited activity in animals, combining it with an existing antiviral drug strongly improved antiviral efficacy. Together, our results reveal a new host pathway that influenza viruses rely on and support host-directed combination approaches to strengthen antiviral treatment and help counter drug resistance.

microbiology↗

bioRxiv2025

Discovery of a Selective Inhibitor of ZIP14 with Therapeutic Potential for Cancer-associated Cachexia

ZIP14/SLC39A14, a membrane-bound metal transporter, is essential for systemic metal homeostasis and has been implicated in inflammatory and metabolic disorders, including cancer-associated cachexia. Despite its biological and therapeutic significance, no selective inhibitors have been identified. Here, we identify 1-phenyl-8-(2-phenylethyl)-1,3,8-triazaspiro[4.5]decan-4-one (PPTD) as the first selective small-molecule inhibitor of ZIP14. PPTD efficiently blocks ZIP14-mediated uptake of zinc, iron, manganese, and cadmium, while sparing the closely related transporter ZIP8/SLC39A8. Mechanistically, PPTD binds specifically to a pocket formed at the dimer interface of ZIP14, as revealed by AlphaFold3 structural prediction, ligand-interaction profiling, structure-activity analyses, and site-directed mutagenesis, providing direct evidence for a targeted inhibition mechanism. ZIP14-driven metal influx promotes reactive oxygen species and lipid peroxidation, leading to cytotoxicity, which PPTD effectively reverses. In vivo, PPTD ameliorates major features of cancer cachexia in mice, including weight loss, reduced survival, muscle wasting, impaired locomotor activity, and disease progression. PPTD thus provides both a chemical probe to dissect ZIP14 function and a potential therapeutic candidate for cancer cachexia, establishing a foundation for the development of therapies targeting ZIP14-mediated metal dysregulation.

biochemistry↗

bioRxiv2022

Discovery of Chlorofluoroacetamide-Based Covalent Inhibitors for SARS-CoV-2 3CL Protease

The pandemic of coronavirus disease 2019 (COVID-19) has urgently necessitated the development of antiviral agents against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The 3C-like protease (3CLpro) is a promising target for COVID-19 treatment. Here, we report the new class of covalent inhibitors for 3CLpro possessing chlorofluoroacetamide (CFA) as a cysteine reactive warhead. Based on the aza-peptide scaffold, we synthesized the series of CFA derivatives in enantiopure form and evaluated their biochemical efficiencies. The data revealed that 8a (YH-6) with R configuration at the CFA unit strongly blocks the SARS-CoV-2 replication in the infected cells and this potency is comparable to that of nirmatrelvir. The X-ray structural analysis shows that 8a (YH-6) forms a covalent bond with Cys145 at the catalytic center of 3CLpro. The strong antiviral activity and sufficient pharmacokinetics property of 8a (YH-6) suggest its potential as a lead compound for treatment of COVID-19.

biochemistry↗

bioRxiv2020

A Large-scale Drug Repositioning Survey for SARS-CoV-2 Antivirals

The emergence of novel SARS coronavirus 2 (SARS-CoV-2) in 2019 has triggered an ongoing global pandemic of severe pneumonia-like disease designated as coronavirus disease 2019 (COVID-19). To date, more than 2.1 million confirmed cases and 139,500 deaths have been reported worldwide, and there are currently no medical countermeasures available to prevent or treat the disease. As the development of a vaccine could require at least 12-18 months, and the typical timeline from hit finding to drug registration of an antiviral is >10 years, repositioning of known drugs can significantly accelerate the development and deployment of therapies for COVID-19. To identify therapeutics that can be repurposed as SARS-CoV-2 antivirals, we profiled a library of known drugs encompassing approximately 12,000 clinical-stage or FDA-approved small molecules. Here, we report the identification of 30 known drugs that inhibit viral replication. Of these, six were characterized for cellular dose-activity relationships, and showed effective concentrations likely to be commensurate with therapeutic doses in patients. These include the PIKfyve kinase inhibitor Apilimod, cysteine protease inhibitors MDL-28170, Z LVG CHN2, VBY-825, and ONO 5334, and the CCR1 antagonist MLN-3897. Since many of these molecules have advanced into the clinic, the known pharmacological and human safety profiles of these compounds will accelerate their preclinical and clinical evaluation for COVID-19 treatment.

microbiology↗

bioRxiv2020

Comparison of de-duplication methods used by WHO Global Antimicrobial Resistance Surveillance System (GLASS) and Japan Nosocomial Infections Surveillance (JANIS) in the surveillance of antimicrobial resistance

A major issue in the surveillance of antimicrobial resistance (AMR) is "de-duplication" or removal of repeated isolates, for which there exist multiple methods. The World Health Organization (WHO) Global Antimicrobial Resistance Surveillance System (GLASS) requires de-duplication by selecting only the first isolate of a given bacterial species per patient per surveillance period per specimen type per age group, gender, and infection origin stratification. However, no study on the comparative application of this method has been reported. The objective of this study was to evaluate differences in data tabulation between the WHO GLASS and the Japan Nosocomial Infections Surveillance (JANIS) system, which counts both patients and isolates after removing repeated isolates of the same bacterial species per multiresistance phenotype isolated from a patient within 30 days, regardless of specimen type. All bacterial data, consisting of approximately 8 million samples from 1795 Japanese hospitals in 2017 were exported from the JANIS database, and were tabulated using either the de-duplication algorithm of GLASS, or JANIS. We compared the tabulated results of the total number of patients whose blood and urine cultures were taken and of the percentage of resistant isolates of Escherichia coli for each priority antibiotic. The number of patients per specimen type tabulated by the JANIS method was always smaller than that of GLASS. There was a small (< 3%) difference in the percentage of resistance of E. coli for any antibiotic between the two methods in both out- and inpatient settings and blood and urine isolates. The two tabulation methods did not show considerable differences in terms of the tabulated percentages of resistance for E. coli. We further discuss how the use of GLASS tabulations to create a public software and website that could help to facilitate the understanding of and treatment against AMR.

microbiology↗