研究者詳細 - 馬場　昌範

論文 - 馬場　昌範

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Hirota Y., Okamoto M., Baba M., Suhara Y. . Potential of fat-soluble vitamins as a platform for antiviral drug development . Bioorganic and Medicinal Chemistry Letters127 130292 - 130292 2025年11月国際誌

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Bioorganic and Medicinal Chemistry Letters

Fat-soluble vitamins, including vitamins A, D, E, and K, exhibit antioxidative, anti-inflammatory, and immunomodulatory effects, making them promising candidates for antiviral drug development. This review highlights their structural features, biological roles, and antiviral potential. Vitamin A derivatives modulate immunity and inhibit viral replication, including SARS-CoV-2. Vitamin D analogs enhance immune responses and target viral enzymes, while vitamin E derivatives reduce oxidative stress and may directly inhibit viral replication. Emerging research on vitamin K derivatives suggests potential antiviral applications. These findings underscore the potential of fat-soluble vitamins as innovative antiviral agents, warranting further investigation to optimize efficacy and clinical use.

DOI： 10.1016/j.bmcl.2025.130292

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Samunuri R., Toyama M., Kasula M., Jha A.K., Okamoto M., Baba M., Sharon A. . Synthesis, Cytotoxicity, and Mechanistic Evaluation of 7-Deazapurine-Based Neplanocin Analogues as Selective Anti-HBV Agents . Chemistryselect10 ( 22 ) 2025年6月

記述言語：日本語出版者・発行元：Chemistryselect

Nucleobase modifications offer a promising route for the discovery of novel antiviral compounds. The synthetic entry of 7H-pyrrolo[2,3-d]pyrimidine with alterations at the 4-position has been thoroughly investigated in the search for bioactive Neplanocin analogs. A key intermediate (4) was synthesized and explored to yield a series of modified carbo-nucleosides (3a–i). Modified 7-deazapurine has been installed to get the targeted 7-deaza carbocyclic nucleosides with an alkyl or aryl. This was accomplished by Pd-cross-coupling reactions with alkyl or aryl organometallics/aryl boronic acids on 7-deazapurines, followed by Mitsunobu coupling and deprotection to produce the final molecules (3a–i). In HBV replication, the anti-HBV activity of 3a–i was evaluated in HepG2.2.15.7 cells. Compounds 3a, 3c, 3d, 3f, 3 g, and 3i showed promise as lead compounds by exhibiting micromolar-level activity on the HBV replicon. The tested compounds demonstrated a dose-dependent inhibition of HBV replication, as demonstrated by the reduced secretion of HBsAg in HepG2.2.15.7 cells, in contrast to the currently approved nucleoside analogue, entecavir (ETV). These findings suggest that the mechanism of action of these analogues is distinct and likely resembles that of previously reported neplanocin derivatives (I & II), which promote the degradation of pregenomic RNA (pgRNA) via a novel pathway. Importantly, S-adenosylhomocysteine hydrolase (SAHase) does not appear to be involved in their antiviral activity, highlighting a unique mechanism for these neplanocin analogues in suppressing HBV replication.

DOI： 10.1002/slct.202500784

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Aoki S., Tanaka T., Yokoi K., Kanbe A., Morita T., Nii M., Satoh H., Kakihana M., Otaki S., Sekiguchi S., Nakamura K., Tojo T., Baba M., Okamoto M. . Design, Synthesis, and Anti-SARS-CoV-2 Activity of Amodiaquine Analogs . Chemical and Pharmaceutical Bulletin73 ( 4 ) 355 - 368 2025年4月

記述言語：日本語出版者・発行元：Chemical and Pharmaceutical Bulletin

The pandemic of coronavirus disease 2019, caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a serious concern worldwide. Although some effective vaccines have been developed, only a few anti-SARS-CoV-2 drugs have been approved for their clinical use. In this study, we designed and synthesized new anti-SARS-CoV-2 drugs based on the chemical structure of amodiaquine, which is known as an antimalarial drug. Consequently, we have identified amodiaquine analogs functionalized with dialkylamino-pendant aminophenol moieties that possess a high level of anti-SARS-CoV-2 activity with a low level of toxicity.

DOI： 10.1248/cpb.c24-00647

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CiNii Research

Kasula M., Toyama M., Samunuri R., Jha A.K., Okamoto M., Baba M., Sharon A. . Pyrazolo[3,4-d]pyrimidine-based neplanocin analogues identified as potential de novo pharmacophores for dual-target HBV inhibition . RSC Medicinal Chemistry16 ( 4 ) 1740 - 1745 2025年2月国際誌

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：RSC Medicinal Chemistry

The discovery of selective and potent inhibitors through de novo pathways is essential to combat drug resistance in chronic hepatitis B (CHB) infections. Recent studies have highlighted that neplanocin A (NepA) derivatives are biologically selective inhibitors of the hepatitis B virus (HBV). In this study, we designed, synthesized, and evaluated various pyrazolo[3,4-d]pyrimidine-based NepA analogues (4a-h) for their anti-HBV activity. Notably, analogue 4g demonstrated significant activity against HBV replication, with EC50 (HBV DNA) = 0.96 μM, CC50 > 100 μM and EC50 (HBsAg) = 0.82 μM, showing selective inhibition of HBsAg secretion. The SAR analysis concluded that replacing the polar 4-NH2 group with -CH3 also acted as a weak H-bonding donor, and the presence of 3-iodo was found to be desirable for the activity/toxicity profile. The nucleoside analogues exhibited a distinct mechanism of action compared to existing nucleoside analogues for the selective inhibition of HBsAg secretion. Based on these findings, compound 4g represents a promising lead molecule for the development of new anti-HBV agents with unique mechanisms of action.

DOI： 10.1039/d4md00932k

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Ishikawa T., Matsumoto K., Hamada T., Koze H., Baba M., Okamoto M., Sudoh M. . In Silico Discovery of SARS-CoV-2 Main Protease Inhibitors Using Docking, Molecular Dynamics, and Fragment Molecular Orbital Calculations . Journal of Physical Chemistry B129 ( 6 ) 1740 - 1749 2025年2月

記述言語：日本語出版者・発行元：Journal of Physical Chemistry B

The 3C-like protease of severe acute respiratory syndrome coronavirus 2, known as the main protease (Mpro), is an attractive drug target for the treatment of coronavirus disease 2019. This study reports the discovery of novel Mpro inhibitors using several in silico techniques, including docking, molecular dynamics (MD), and fragment molecular orbital (FMO) calculations. We performed docking calculations on 5950 compounds with bioactivity, and 12 compounds were selected. An enzymatic assay was conducted, revealing that BP-1-102 exhibits significant Mpro inhibitory activity with an IC50 of 11.1 μM. The identification of seed compounds from the experiments on a few compounds demonstrates the effectiveness of our docking calculations. Furthermore, the detailed analyses using MD and FMO calculations suggested an interaction mechanism in which the hydroxyl group of BP-1-102 forms a hydrogen bond with E166 of Mpro. The Mpro inhibitory activity of SH-4-54, a derivative without the aforementioned hydroxyl group, was investigated and observed to be significantly reduced, with an IC50 of 81.5 μM. This result strongly supports the suggested interaction mechanism.

DOI： 10.1021/acs.jpcb.4c07920

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Koze H., Sudoh M., Onitsuka S., Okamura H., Ishikawa T., Tani F., Miyata-Yabuki Y., Shirouzu M., Baba M., Okamoto M., Hamada T. . Sulfoquinovosyl diacylglycerol, a component of Holy Basil Ocimum tenuiflorum, inhibits the activity of the SARS-CoV-2 main protease and viral replication in vitro . Journal of Natural Medicines79 ( 1 ) 122 - 133 2025年1月

記述言語：日本語出版者・発行元：Journal of Natural Medicines

The persistence of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the emergence of new mutant strains continue to present a substantial threat with potential for future pandemics. Safe, effective, and readily available COVID-19 therapeutics are urgently needed to prepare for future coronavirus pandemics. To help identify new antiviral agents, the present study focused on natural products in the extracts of Holy Basil, Ocimum tenuiflorum L., which show potential inhibitory effects against the SARS-CoV-2 main protease (Mpro). Bioassay-guided isolation of the MeOH extracts of O. tenuiflorum led to the identification of a sulfur-containing glyceroglycolipid, sulfoquinovosyl diacylglycerol (SQDG: 1), as a potent Mpro inhibitor that effectively inhibited Mpro activity (IC50: 0.42 µM). SQDG (1) also markedly suppressed SARS-CoV-2 replication (EC50, 51.2 µM) in vitro while displaying no cytotoxicity (CC50 > 100 µM). Further inhibition kinetic studies and docking simulations clearly demonstrated that SQDG strongly inhibited SARS-CoV-2 Mproin a competitive and mixed-inhibition manner. These findings highlight SQDG as a promising lead compound for COVID-19 therapy and emphasize the need to explore new drugs from natural sources.

DOI： 10.1007/s11418-024-01855-6

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Homma T, Okamoto M, Koharazawa R, Hayakawa M, Fushimi T, Tode C, Hirota Y, Osakabe N, Baba M, Suhara Y . Exploring Novel Vitamin K Derivatives with Anti-SARS-CoV-2 Activity. . ACS omega8 ( 45 ) 42248 - 42263 2023年11月査読国際誌

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ACS Omega

From our compound library of vitamin K derivatives, we found that some compounds exhibited anti-SARS-CoV-2 activity in VeroE6/TMPRSS2 cells. The common structure of these compounds was menaquinone-2 (MK-2) with either the m-methylphenyl or the 1-naphthyl group introduced at the end of the side chain. Therefore, new vitamin K derivatives having more potent anti-SARS-CoV-2 activity were explored by introducing various functional groups at the ω-position of the side chain. MK-2 derivatives with a purine moiety showed the most potent antiviral activity among the derivatives. We also found that their mechanism of action was the inhibition of RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2. The chemical structures of our compounds were completely different from those of nucleic acid derivatives such as remdesivir and molnupiravir, clinically approved RdRp inhibitors for COVID-19 treatment, suggesting that our compounds may be effective against viruses resistant to these nucleic acid derivatives.

DOI： 10.1021/acsomega.3c04175

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小原沢諒人, 岡本実佳, 本間大暉, 早川真由, 廣田佳久, 馬場昌範, 須原義智 . 抗SARS-CoV-2活性を有するビタミンK誘導体の創製 . ビタミン97 ( 4 ) 228 - 228 2023年4月

Baba M., Okamoto M., Toyama M., Sakakibara N., Shimojima M., Saijo M., Niwa T., Yagi Y. . Amodiaquine derivatives as inhibitors of severe fever with thrombocytopenia syndrome virus (SFTSV) replication . Antiviral Research210 105479 - 105479 2023年2月国際誌

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Antiviral Research

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne viral infection caused by a bandavirus in the family of Phenuiviridae, commonly known as SFTS virus (SFTSV). We have previously isolated SFTSV from blood samples of SFTS patients and established an antiviral assay system to identify selective inhibitors of SFTSV in vitro. Using the assay system, the antimalarial agent amodiaquine was identified as a selective inhibitor of SFTSV replication. However, due to its insufficient antiviral activity, 98 amodiaquine derivatives were newly synthesized and examined for their anti-SFTSV activity. Among the derivatives, some compounds showed selective inhibitory effect on SFTSV replication in vitro. The 50% effective concentration (EC50) and cytotoxic concentration (CC50) of the most active compound (C-90) were 2.6 ± 0.6 and >50 μM, respectively. This EC50 value was comparable to or slightly better than that of favipiravir (4.1 ± 0.6 μM). On the other hand, pharmacokinetic studies in vivo revealed that C-90 was poor in its oral bioavailability in mice. Therefore, we further designed and synthesized derivatives and obtained 2 compounds with selective anti-SFTSV activity in vitro and improved pharmacokinetics in vivo.

DOI： 10.1016/j.antiviral.2022.105479

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Kajiya T, Sawayama H, Arima E, Okamoto M, Baba M, Toyama M, Okuya K, Ozawa M, Atsuchi N, Nishi J, Suda Y . Novel RT-PCR Using Sugar Chain-Immobilized Gold-Nanoparticles Correlates Patients' Symptoms: The Follow-Up Study of COVID-19 Hospitalized Patients. . Viruses14 ( 11 ) 2577 - 2577 2022年11月査読

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Viruses

Background: The transmissible capacity and toxicity of SARS-CoV-2 variants are continually changing. We report here the follow-up study of hospitalized COVID-19 patients from 2020 to 2022. It is known that the PCR diagnosis for hospitalized patients sometimes causes confusion because of the incompatibility between their diagnosis and symptoms. We applied our sugar chain-immobilized gold-nanoparticles for the extraction and partial purification of RNA from specimens for quantitative RT-PCR assay and evaluated whether the results correlate with patients' symptoms. Methods and Results: Saliva specimens were taken from hospitalized patients with mild or moderate symptoms every early morning. At the time of RT-PCR diagnosis, two methods for the extraction and partial purification of RNA from the specimen were performed: a commonly used Boom (Qiagen) method and our original sugar chain-immobilized gold nanoparticle (SGNP) method. For symptoms, body temperature and oxygen saturation (SpO2) of patients were monitored every 4 h. Conclusions: It was clear that patients infected with the Delta variant needed more time to recover than those with the Omicron variant, and that the SGNP method showed more realistic correlation with the symptoms of patients compared with the common Qiagen method.

DOI： 10.3390/v14112577

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Toyama M., Watashi K., Ikeda M., Yamashita A., Okamoto M., Moriishi K., Muramatsu M., Wakita T., Sharon A., Baba M. . Novel Neplanocin A Derivatives as Selective Inhibitors of Hepatitis B Virus with a Unique Mechanism of Action . Antimicrobial Agents and Chemotherapy66 ( 6 ) e0207321 2022年6月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Antimicrobial Agents and Chemotherapy

Novel neplanocin A derivatives have been identified as potent and selective inhibitors of hepatitis B virus (HBV) replication in vitro. These include (1S,2R,5R)-5-(5-bromo-4- methyl-7H-pyrrolo[2,3-d]-pyrimidin-7-yl)-3-(hydroxymethyl)cyclopent-3-ene-1,2-diol (AR-II-04-26) and (1S,2R,5R)-5-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-(hydroxylmethyl) cyclopent-3-ene-1,2-diol (MK-III-02-03). The 50% effective concentrations of AR-II-04-26 and MK-III-02-03 were 0.77 6 0.23 and 0.83 6 0.36 mM in HepG2.2.15.7 cells, respectively. These compounds reduced intracellular HBV RNA levels in HepG2.2.15.7 cells and infected primary human hepatocytes. Accordingly, they could reduce HBs and HBe antigen production in the culture supernatants, which was not observed with clinically approved anti-HBV nucleosides and nucleotides (reverse transcriptase inhibitors). The neplanocin A derivatives also inhibited HBV RNA derived from cccDNA. In addition, unlike neplanocin A itself, the compounds did not inhibit S-adenosyl-L-homocysteine hydrolase activity. Thus, it appears that the mechanism of action of AR-II-04-26 and MK-III-02-03 differs from that of the clinically approved anti-HBV agents. Although their exact mechanism (target molecule) remains to be elucidated, the novel neplanocin A derivatives are considered promising candidate drugs for inhibition of HBV replication.

DOI： 10.1128/aac.02073-21

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本間大暉, 岡本実佳, 馬場昌範, 須原義智 . 抗ウイルス活性を有する新規ビタミン誘導体の研究 . ビタミン96 ( 4 ) 189 - 189 2022年4月

Ukawa M, Endo R, Yagi H, Tomono T, Miyata K, Shigeno K, Tobita E, Uto T, Baba M, Sakuma S . Mechanism on antigen delivery under mucosal vaccination using cell-penetrating peptides immobilized at multiple points on polymeric platforms. . International journal of pharmaceutics613 121376 - 121376 2022年2月国際誌

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：International Journal of Pharmaceutics

We have developed an aggregate of D-octaarginine immobilized at multiple points on a co-polymer of N-vinylacetamide and acrylic acid. Previous studies revealed that immunoglobulin G and A were induced when mice were inoculated with influenza virus antigens under coadministration with the D-octaarginine-immobilized polymers as a mucosal vaccine adjuvant. Infection experiments demonstrated that mice vaccinated with a mixture of inactivated influenza viruses and the polymers were protected from infection with mouse-adapted infectious viruses. In the present study, we investigated the mechanism on antigen delivery under mucosal vaccination using the polymers. Two-hour retention of fluorescein-labeled ovalbumin (F-OVA) on the nasal mucosa was observed when applied with the polymers; nevertheless F-OVA was eliminated less than 10 min under polymer-free conditions. F-OVA mixed with the polymers was vigorously taken up into murine dendritic cells. Electrophoresis and dynamic light scattering analysis indicated that OVA interacted with the polymers. The uptake of F-OVA was hardly ever inhibited by the addition of an excess amount of intact OVA. The results suggested that viral antigens were accumulated on the mucosa and delivered into dendritic cells under basolateral membranes via dendrites extending to the mucosal surface and/or subsequent to their permeation through epithelial cells, when they were coadministered with D-octaarginine-immobilized polymers.

DOI： 10.1016/j.ijpharm.2021.121376

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Okamoto M. . Induction of E. coli-derived endonuclease MazF suppresses HIV-1 production and causes apoptosis in latently infected cells . Biochemical and Biophysical Research Communications530 ( 3 ) 597 - 602 2020年9月査読

Yokota R. . Novel anti-CD70 antibody drug conjugate for the treatment of adult T-cell leukemia (ATL) . Anticancer Research40 ( 8 ) 4471 - 4479 2020年8月査読

Okamoto M. . The chemokine receptor antagonist cenicriviroc inhibits the replication of SARS-CoV-2 in vitro . Antiviral Research182 104902 - 104902 2020年7月査読

Samunuri R. . Synthesis and anti-HBV activity of carbocyclic nucleoside hybrids with salient features of entecavir and aristeromycin . RSC Medicinal Chemistry11 ( 5 ) 597 - 601 2020年5月査読

Furukawa Y. . Successful treatment of an AIDS patient with prolonged Mycobacterium avium bacteremia, high HIV RNA, HBV infection, Kaposi's sarcoma and cytomegalovirus retinitis . Journal of Infection and Chemotherapy26 ( 2 ) 279 - 281 2020年2月招待査読

Tanishita S. . Cross-Protective Abilities of Hyaluronic Acid Modified with Tetraglycine- l -octaarginine as a Mucosal Adjuvant against Infection with Heterologous Influenza Viruses . Bioconjugate Chemistry30 ( 12 ) 3028 - 3037 2019年12月招待査読

Toyama M. . Pyrimidotriazine derivatives as selective inhibitors of HBV capsid assembly . Virus Research271 197677 - 197677 2019年10月招待査読

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