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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (15 March 2024) | Viewed by 12701

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Prof. Dr. Kohji Noguchi

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Department of Pharmacy, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Tokyo, Japan
Interests: molecular target; virology; cancer

Special Issue Information

Dear Colleagues,

Viral infections are diseases that cause harmful human symptoms caused by the virus, and pathogen-specific molecules are excellent targets for drug treatment. Some cancers are caused by pathogen infections, and various genetic abnormalities can be cancer-specific molecular targets. Even if the cause of the disease is known, it is not easy to develop an actual therapeutic drug. Drug resistance is also an important clinical issue. In order to develop various therapeutic agents, it is important to clarify various promising therapeutic target molecules. We would like to contribute to the next generation of drug discovery by elucidating new molecular targets related to emerging infectious diseases and cancer.

Prof. Dr. Kohji Noguchi
Guest Editor

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Keywords

anticancer drugs
antiviral drugs
molecular targets

Published Papers (6 papers)

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Research

19 pages, 2707 KiB

Open AccessArticle

Pharmacological Targeting of Bcl-2 Induces Caspase 3-Mediated Cleavage of HDAC6 and Regulates the Autophagy Process in Colorectal Cancer

by Donglin Yang, Liujun He, Shuiqing Ma, Shiqiang Li, Yajun Zhang, Chunsheng Hu, Jiuhong Huang, Zhigang Xu, Dianyong Tang and Zhongzhu Chen

Int. J. Mol. Sci. 2023, 24(7), 6662; https://doi.org/10.3390/ijms24076662 - 3 Apr 2023

Cited by 4 | Viewed by 1822

Abstract

Compound 6d, a spiroindoline compound, exhibits antiproliferative capability against cancer cell lines. However, the exact underlying mechanism of this compound-mediated inhibitory capability remains unclear. Here, we showed that compound 6d is an inhibitor of Bcl-2, which suppresses CRC growth by inducing caspase 3-mediated intrinsic apoptosis of mitochondria. Regarding the underlying mechanism, we identified HDAC6 as a direct substrate for caspase 3, and caspase 3 activation induced by compound 6d directly cleaves HDAC6 into two fragments. Moreover, the cleavage site was located at D1088 in the DMAD-S motif HDAC6. Apoptosis stimulated by compound 6d promoted autophagy initiation by inhibiting interaction between Bcl-2 and Beclin 1, while it led to the accumulation of ubiquitinated proteins and the reduction of autophagic flux. Collectively, our findings reveal that the Bcl-2-caspase 3-HDAC6 cascade is a crucial regulatory pathway of autophagy and identify compound 6d as a novel lead compound for disrupting the balance between apoptosis and autophagy. Full article

(This article belongs to the Special Issue Molecular Targets for Antiviral and Anticancer Drugs)

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22 pages, 90605 KiB

Open AccessArticle

N,Nʹ-Diarylurea Derivatives (CTPPU) Inhibited NSCLC Cell Growth and Induced Cell Cycle Arrest through Akt/GSK-3β/c-Myc Signaling Pathway

by Sunisa Thongsom, Satapat Racha, Zin Zin Ei, Korrakod Petsri, Nithikoon Aksorn, Supakarn Chamni, Vitsarut Panpuang, Hongbin Zou and Pithi Chanvorachote

Int. J. Mol. Sci. 2023, 24(2), 1357; https://doi.org/10.3390/ijms24021357 - 10 Jan 2023

Cited by 3 | Viewed by 2407

Abstract

Lung cancer is one of the most common malignancies worldwide. Non-small-cell lung cancer (NSCLC) accounts for more than 80% of lung cancers, shows chemotherapy resistance, metastasis, and relapse. The phosphatidylinositol-3 kinase (PI3K)/Akt pathway has been implicated in the carcinogenesis and disease progression of NSCLC, suggesting that it may be a promising therapeutic target for cancer therapy. Although phenylurea derivatives have been reported as potent multiple kinase inhibitors, novel unsymmetrical N,Nʹ-diarylurea derivatives targeting the PI3K/Akt pathway in NSCLC cells remain unknown. Methods: N,Nʹ-substituted phenylurea derivatives CTPPU and CT-(4-OH)-PU were investigated for their anticancer proliferative activity against three NSCLC cell lines (H460, A549, and H292) by 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide, colony formation, Hoechst33342/PI staining assays, and apoptosis analysis. The protein expressions of Akt pathway-related proteins in response to CTPPU or CT-(4-OH)-PU were detected by Western blot analysis. The Kyoto Encyclopedia of Genes and Genomes mapper was used to identify the possible signaling pathways in NSCLC treated with CTPPU. The cell cycle was analyzed by flow cytometry. Molecular docking was used to investigate the possible binding interaction of CTPPU with Akt, the mammalian target of rapamycin complex 2 (mTORC2), and PI3Ks. Immunofluorescence and Western blot analysis were used to validate our prediction. Results: The cytotoxicity of CTPPU was two-fold higher than that of CT-(4-OH)-PU for all NSCLC cell lines. Similarly, the non-cytotoxic concentration of CTPPU (25 µM) dramatically inhibited the colony formation of NSCLC cells, whereas its relative analog CT-(4-OH)-PU had no effect. Protein analysis revealed that Akt and its downstream effectors, namely, phosphorylated glycogen synthase kinase (GSK)-3β (Ser9), β-catenin, and c-Myc, were reduced in response to CTPPU treatment, which suggested the targeting of Akt-dependent pathway, whereas CT-(4-OH)-PU had no effect on such cell growth regulatory signals. CTPPU induced G1/S cell cycle arrest in lung cancer cells. Immunofluorescence revealed that CTPPU decreased p-Akt and total Akt protein levels, which implied the effect of the compound on protein activity and stability. Next, we utilized in silico molecular docking analysis to reveal the potential molecular targets of CTPPU, and the results showed that the compound could specifically bind to the allosteric pocket of Akt and three sites of mTORC2 (catalytic site, A-site, and I-site), with a binding affinity greater than that of reference compounds. The compound cannot bind to PI3K, an upstream regulator of the Akt pathway. The effect of CTPPU on PI3K and Akt was confirmed. This finding indicated that the compound could decrease p-Akt but caused no effect on p-PI3K. Conclusions: The results indicate that CTPPU significantly inhibits NSCLC cell proliferation by inducing G1/S cell cycle arrest via the Akt/GSK-3β/c-Myc signaling pathway. Molecular docking revealed that CTPPU could interact with Akt and mTORC2 molecules with a high binding affinity. These data indicate that CTPPU is a potential novel alternative therapeutic approach for NSCLC. Full article

(This article belongs to the Special Issue Molecular Targets for Antiviral and Anticancer Drugs)

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21 pages, 4892 KiB

Open AccessArticle

Kaposi’s Sarcoma-Associated Herpesvirus ORF21 Enhances the Phosphorylation of MEK and the Infectivity of Progeny Virus

by Tatsuo Yamaguchi, Tadashi Watanabe, Yuki Iwaisako and Masahiro Fujimuro

Int. J. Mol. Sci. 2023, 24(2), 1238; https://doi.org/10.3390/ijms24021238 - 8 Jan 2023

Cited by 3 | Viewed by 1532

Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8, is the causative agent of Kaposi’s sarcoma, Castleman’s disease, and primary effusion lymphoma. Although the functions of the viral thymidine kinases (vTK) of herpes simplex virus-1/2 are well understood, that of KSHV ORF21 (an ortholog of vTK) is largely unknown. Here, we investigated the role of ORF21 in lytic replication and infection by generating two ORF21-mutated KSHV BAC clones: ORF21-kinase activity deficient KSHV (21KD) and stop codon-induced ORF21-deleted KSHV (21del). The results showed that both ORF21 mutations did not affect viral genome replication, lytic gene transcription, or the production of viral genome-encapsidated particles. The ORF21 molecule-dependent function, other than the kinase function of ORF21, was involved in the infectivity of the progeny virus. ORF21 was expressed 36 h after the induction of lytic replication, and endogenously expressed ORF21 was localized in the whole cytoplasm. Moreover, ORF21 upregulated the MEK phosphorylation and anchorage-independent cell growth. The inhibition of MEK signaling by U0126 in recipient target cells suppressed the number of progeny virus-infected cells. These suggest that ORF21 transmitted as a tegument protein in the progeny virus enhances the new infection through MEK up-regulation in the recipient cell. Our findings indicate that ORF21 plays key roles in the infection of KSHV through the manipulation of the cellular function. Full article

(This article belongs to the Special Issue Molecular Targets for Antiviral and Anticancer Drugs)

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9 pages, 2149 KiB

Open AccessArticle

Foretinib Is Effective against Triple-Negative Breast Cancer Cells MDA-MB-231 In Vitro and In Vivo by Down-Regulating p-MET/HGF Signaling

by Xiwei Ji, Xiangrui Meng, Qingfeng He, Xiaoqiang Xiang, Yufei Shi and Xiao Zhu

Int. J. Mol. Sci. 2023, 24(1), 757; https://doi.org/10.3390/ijms24010757 - 1 Jan 2023

Cited by 1 | Viewed by 2410

Abstract

This study investigated the antitumor effects of foretinib on triple-negative breast cancer cells MDA-MB-231 xenograft tumors in vivo underlying phosphorylated mesenchymal to epithelial transition (p-MET)/ hepatocyte growth factor (HGF)-related mechanism, as well as its pharmacokinetic characteristics. The MDA-MB-231 human breast cancer cell line was used for in vitro experiments, and the tumor xenograft model was established for in vivo experiments. MDA-MB-231 xenograft mice received oral foretinib (15 or 50 mg/kg/day) or vehicle for 18 days. The xenograft tumors were collected. Protein expressions of p-MET and HGF were examined with Western blotting and immunohistochemical staining. The mRNA expression of MET was examined with real-time PCR. Blood samples were collected from the mice treated with foretinib under different doses of 2, 10, and 50 mg/kg, and the pharmacokinetic profiles of foretinib were evaluated. We found that foretinib treatment caused a significant inhibition in tumor growth in a dose-dependent manner, whereas the continuous administration did not result in weight loss in treated nude mice. In both MDA-MB-231 cells and xenograft tumors, foretinib suppressed the expression of p-MET and HGF. These findings reveal that the decrease of p-MET and HGF may play an important role in the anti-breast cancer properties of foretinib. Full article

(This article belongs to the Special Issue Molecular Targets for Antiviral and Anticancer Drugs)

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15 pages, 2151 KiB

Open AccessArticle

Direct Inhibition of SARS-CoV-2 Spike Protein by Peracetic Acid

by Yuichiro Yamamoto, Yoshio Nakano, Mana Murae, Yoshimi Shimizu, Shota Sakai, Motohiko Ogawa, Tomoharu Mizukami, Tetsuya Inoue, Taishi Onodera, Yoshimasa Takahashi, Takaji Wakita, Masayoshi Fukasawa, Satoru Miyazaki and Kohji Noguchi

Int. J. Mol. Sci. 2023, 24(1), 20; https://doi.org/10.3390/ijms24010020 - 20 Dec 2022

Cited by 4 | Viewed by 2007

Abstract

Peracetic acid (PAA) disinfectants are effective against a wide range of pathogenic microorganisms, including bacteria, fungi, and viruses. Several studies have shown the efficacy of PAA against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); however, its efficacy in SARS-CoV-2 variants and the molecular mechanism of action of PAA against SARS-CoV-2 have not been investigated. SARS-CoV-2 infection depends on the recognition and binding of the cell receptor angiotensin-converting enzyme 2 (ACE2) via the receptor-binding domain (RBD) of the spike protein. Here, we demonstrated that PAA effectively suppressed pseudotyped virus infection in the Wuhan type and variants, including Delta and Omicron. Similarly, PAA reduced the authentic viral load of SARS-CoV-2. Computational analysis suggested that the hydroxyl radicals produced by PAA cleave the disulfide bridges in the RBD. Additionally, the PAA treatment decreased the abundance of the Wuhan- and variant-type spike proteins. Enzyme-linked immunosorbent assay showed direct inhibition of RBD-ACE2 interactions by PAA. In conclusion, the PAA treatment suppressed SARS-CoV-2 infection, which was dependent on the inhibition of the interaction between the spike RBD and ACE2 by inducing spike protein destabilization. Our findings provide evidence of a potent disinfection strategy against SARS-CoV-2. Full article

(This article belongs to the Special Issue Molecular Targets for Antiviral and Anticancer Drugs)

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14 pages, 3026 KiB

Open AccessArticle

Antiviral Activity of N₁,N₃-Disubstituted Uracil Derivatives against SARS-CoV-2 Variants of Concern

by Andrei E. Siniavin, Mikhail S. Novikov, Vladimir A. Gushchin, Alexander A. Terechov, Igor A. Ivanov, Maria P. Paramonova, Elena S. Gureeva, Leonid I. Russu, Nadezhda A. Kuznetsova, Elena V. Shidlovskaya, Sergei I. Luyksaar, Daria V. Vasina, Sergei A. Zolotov, Nailya A. Zigangirova, Denis Y. Logunov and Alexander L. Gintsburg

Int. J. Mol. Sci. 2022, 23(17), 10171; https://doi.org/10.3390/ijms231710171 - 5 Sep 2022

Cited by 8 | Viewed by 1817

Abstract

Despite the widespread use of the COVID-19 vaccines, the search for effective antiviral drugs for the treatment of patients infected with SARS-CoV-2 is still relevant. Genetic variability leads to the continued circulation of new variants of concern (VOC). There is a significant decrease in the effectiveness of antibody-based therapy, which raises concerns about the development of new antiviral drugs with a high spectrum of activity against VOCs. We synthesized new analogs of uracil derivatives where uracil was substituted at the N₁ and N₃ positions. Antiviral activity was studied in Vero E6 cells against VOC, including currently widely circulating SARS-CoV-2 Omicron. All synthesized compounds of the panel showed a wide antiviral effect. In addition, we determined that these compounds inhibit the activity of recombinant SARS-CoV-2 RdRp. Our study suggests that these non-nucleoside uracil-based analogs may be of future use as a treatment for patients infected with circulating SARS-CoV-2 variants. Full article

(This article belongs to the Special Issue Molecular Targets for Antiviral and Anticancer Drugs)

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