Identification of Diaryl-Quinoline Compounds as Entry Inhibitors of Ebola Virus

Ebola virus is the causative agent of Ebola virus disease in humans. The lethality of Ebola virus infection is about 50%, supporting the urgent need to develop anti-Ebola drugs. Glycoprotein (GP) is the only surface protein of the Ebola virus, which is functionally critical for the virus to attach and enter the host cells, and is a promising target for anti-Ebola virus drug development. In this study, using the recombinant HIV-1/Ebola pseudovirus platform we previously established, we evaluated a small molecule library containing various quinoline compounds for anti-Ebola virus entry inhibitors. Some of the quinoline compounds specifically inhibited the entry of the Ebola virus. Among them, compound SYL1712 was the most potent Ebola virus entry inhibitor with an IC50 of ~1 μM. The binding of SYL1712 to the vial glycoprotein was computationally modeled and was predicted to interact with specific residues of GP. We used the time of the addition assay to show that compound SYL1712 blocks Ebola GP-mediated entry. Finally, consistent with being an Ebola virus entry inhibitor, compound SYL1712 inhibited infectious Ebola virus replication in tissue culture under biosafety level 4 containment, with an IC50 of 2 μM. In conclusion, we identified several related molecules with a diaryl-quinoline scaffold as potential anti-EBOV entry inhibitors, which can be further optimized for anti-Ebola drug development.

Download Full-text

Identification of Potent Ebola Virus Entry Inhibitors with Suitable Properties for in Vivo Studies

Journal of Medicinal Chemistry ◽

10.1021/acs.jmedchem.8b00704 ◽

2018 ◽

Vol 61 (14) ◽

pp. 6293-6307 ◽

Cited By ~ 7

Author(s):

Hu Liu ◽

Ye Tian ◽

Kyungae Lee ◽

Pranav Krishnan ◽

May Kwang-Mei Wang ◽

...

Keyword(s):

Ebola Virus ◽

Virus Entry ◽

In Vivo Studies ◽

Entry Inhibitors ◽

Virus Entry Inhibitors

Download Full-text

Chemical and Structural Aspects of Ebola Virus Entry Inhibitors

ACS Infectious Diseases ◽

10.1021/id500025n ◽

2014 ◽

Vol 1 (1) ◽

pp. 42-52 ◽

Cited By ~ 24

Author(s):

Elisabeth K. Nyakatura ◽

Julia C. Frei ◽

Jonathan R. Lai

Keyword(s):

Ebola Virus ◽

Virus Entry ◽

Entry Inhibitors ◽

Virus Entry Inhibitors ◽

Structural Aspects

Download Full-text

Mining of Ebola virus entry inhibitors identifies approved drugs as two-pore channel pore blockers

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research ◽

10.1016/j.bbamcr.2018.10.022 ◽

2019 ◽

Vol 1866 (7) ◽

pp. 1151-1161 ◽

Cited By ~ 12

Author(s):

Christopher J. Penny ◽

Kristin Vassileva ◽

Archana Jha ◽

Yu Yuan ◽

Xavier Chee ◽

...

Keyword(s):

Ebola Virus ◽

Virus Entry ◽

Pore Channel ◽

Channel Pore ◽

Entry Inhibitors ◽

Virus Entry Inhibitors ◽

Approved Drugs

Download Full-text

Challenges and perspectives in the discovery of dengue virus entry inhibitors

Current Medicinal Chemistry ◽

10.2174/0929867328666210521213118 ◽

2021 ◽

Vol 28 ◽

Author(s):

Facundo N. Gallo ◽

Ana G. Enderle ◽

Lucas A. Pardo ◽

Emilse S. Leal ◽

Mariela Bollini

Keyword(s):

Dengue Virus ◽

Rational Design ◽

Viral Infections ◽

Virus Entry ◽

Antiviral Treatment ◽

Antiviral Agent ◽

Cellular Protein ◽

Host Cells ◽

Entry Inhibitors ◽

Virus Entry Inhibitors

: Dengue virus (DENV) disease has become one of the major challenges in public health. Currently, there is no antiviral treatment for this infection. Since human transmission occurs via mosquitoes of the Aedes genus, most efforts have been focused on controlling this vector. However, these control strategies have not been totally successful, as reflected in the increasing number of DENV infections per year, becoming an endemic disease in more than 100 countries worldwide. Consequently, the development of a safe antiviral agent is urgently needed. In this sense, rational design approaches have been applied in the development of antiviral compounds that inhibit one or more steps in the viral replication cycle. The entry of viruses into host cells is an early and specific stage of infection. Targeting either viral components or cellular protein targets is an affordable and effective strategy for therapeutic intervention of viral infections. This review provides an extensive overview of the small organic molecules, peptides, and inorganic moieties that have been tested so far as DENV entry direct-acting antiviral agents. The latest advances based on computer-aided drug design (CADD) strategies and traditional medicinal chemistry approaches in the design and evaluation of DENV virus entry inhibitors will be discussed. Furthermore, physicochemical drug properties such as solubility, lipophilicity, stability, and current results of pre-clinical and clinical studies will also be discussed in detail.

Download Full-text

Synthesis of Four Pentacyclic Triterpene–Sialylglycopeptide Conjugates and Their Affinity Assays with Hemagglutinin

Molecules ◽

10.3390/molecules26040895 ◽

2021 ◽

Vol 26 (4) ◽

pp. 895

Author(s):

Mei Luo ◽

Ximin Wu ◽

Yiming Li ◽

Fujiang Guo

Keyword(s):

Influenza Virus ◽

Virus Entry ◽

Cycloaddition Reaction ◽

Pentacyclic Triterpene ◽

Entry Inhibitors ◽

Important Target ◽

Virus Entry Inhibitors ◽

Influenza Outbreaks ◽

Ha Protein ◽

Dissociation Constant Kd

Influenza outbreaks pose a serious threat to human health. Hemagglutinin (HA) is an important target for influenza virus entry inhibitors. In this study, we synthesized four pentacyclic triterpene conjugates with a sialylglycopeptide scaffold through the Cu(I)-catalyzed alkyne-azide cycloaddition reaction (CuAAC) and prepared affinity assays of these conjugates with two HAs, namely H1N1 (A/WSN/1933) and H5N1 (A/Hong Kong/483/97), respectively. With a dissociation constant (KD) of 6.89 μM, SCT-Asn-betulinic acid exhibited the strongest affinity with the H1N1 protein. Furthermore, with a KD value of 9.10 μM, SCT-Asn-oleanolic acid exhibited the strongest affinity with the H5N1 protein. The conjugates considerably enhanced antiviral activity, which indicates that pentacyclic triterpenes can be used as a ligand to improve the anti-influenza ability of the sialylglycopeptide molecule by acting on the HA protein.

Download Full-text

Statement of retraction: [thiophen urea derivatives as a new class of hepatitis C virus entry inhibitors]

Journal of Enzyme Inhibition and Medicinal Chemistry ◽

10.1080/14756366.2021.1927378 ◽

2021 ◽

Vol 36 (1) ◽

pp. 1048-1048

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Virus Entry ◽

Urea Derivatives ◽

Entry Inhibitors ◽

New Class ◽

Virus Entry Inhibitors

Download Full-text

Identification of Ellagic Acid from Plant Rhodiola rosea L. as an Anti-Ebola Virus Entry Inhibitor

Viruses ◽

10.3390/v10040152 ◽

2018 ◽

Vol 10 (4) ◽

pp. 152 ◽

Cited By ~ 16

Author(s):

Qinghua Cui ◽

Ruikun Du ◽

Manu Anantpadma ◽

Adam Schafer ◽

Lin Hou ◽

...

Keyword(s):

Ellagic Acid ◽

Ebola Virus ◽

Virus Entry ◽

Rhodiola Rosea ◽

Entry Inhibitor

Download Full-text

Reply to Padmanabhan and Dixit: Hepatitis C virus entry inhibitors for optimally boosting direct-acting antiviral-based treatments

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1705234114 ◽

2017 ◽

Vol 114 (23) ◽

pp. E4527-E4529 ◽

Cited By ~ 7

Author(s):

Hirofumi Ohashi ◽

Yoshiki Koizumi ◽

Kento Fukano ◽

Takaji Wakita ◽

Alan S. Perelson ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Virus Entry ◽

Direct Acting Antiviral ◽

Entry Inhibitors ◽

Virus Entry Inhibitors ◽

Direct Acting

Download Full-text

Structural Basis for the Understanding of Entry Inhibitors Against SARS Viruses

Current Medicinal Chemistry ◽

10.2174/0929867328666210514122418 ◽

2021 ◽

Vol 28 ◽

Author(s):

Prem Kumar Kushwaha ◽

Neha Kumari ◽

Sneha Nayak ◽

Keshav Kishor ◽

Ashoke Sharon

Keyword(s):

Viral Entry ◽

Molecular Level ◽

Virus Entry ◽

Holistic Approach ◽

Symptomatic Treatment ◽

Host Cells ◽

Structural Basis ◽

Viral Fusion ◽

Structural Studies ◽

Entry Inhibitors

: Outbreaks due to Severe Acute Respiratory Syndrome-Corona virus 2 (SARS-CoV-2) initiated in Wuhan city, China, in December 2019 which continued to spread internationally, posing a pandemic threat as declared by WHO and as of March 10, 2021, confirmed cases reached 118 million along with 2.6 million deaths worldwide. In the absence of specific antiviral medication, symptomatic treatment and physical isolation remain the options to control the contagion. The recent clinical trials on antiviral drugs highlighted some promising compounds such as umifenovir (haemagglutinin-mediated fusion inhibitor), remdesivir (RdRp nucleoside inhibitor), and favipiravir (RdRp Inhibitor). WHO launched a multinational clinical trial on several promising analogs as a potential treatment to combat SARS infection. This situation urges a holistic approach to invent safe and specific drugs as a prophylactic and therapeutic cure for SARS-related-viral diseases, including COVID-19. : It is significant to note that researchers worldwide have been doing their best to handle the crisis and have produced an extensive and promising literature body. It opens a scope and allows understanding the viral entry at the molecular level. A structure-based approach can reveal the molecular-level understanding of viral entry interaction. The ligand profiling and non-covalent interactions among participating amino-acid residues are critical information to delineate a structural interpretation. The structural investigation of SARS virus entry into host cells will reveal the possible strategy for designing drugs like entry inhibitors. : The structure-based approach demonstrates details at the 3D molecular level. It shows specificity about SARS-CoV-2 spike interaction, which uses human angiotensin-converting enzyme 2 (ACE2) as a receptor for entry, and the human protease completes the process of viral fusion and infection. : The 3D structural studies reveal the existence of two units, namely S1 and S2. S1 is called a receptor-binding domain (RBD) and responsible for interacting with the host (ACE2), and the S2 unit participates in the fusion of viral and cellular membranes. TMPRSS2 mediates the cleavage at S1/S2 subunit interface in S-protein of SARS CoV-2, leading to viral fusion. Conformational difference associated with S1 binding alters ACE2 interaction and inhibits viral fusion. Overall, the detailed 3D structural studies help understand the 3D structural basis of interaction between viruses with host factors and available scope for the new drug discovery process targeting SARS-related virus entry into the host cell.

Download Full-text