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Design, Synthesis and Bioactivity Evaluation of Target-Based Antiviral Drugs
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Design, Synthesis and Bioactivity Evaluation of Target-Based Antiviral Drugs

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 17854

Special Issue Editors

Prof. Dr. Peng Zhan

E-Mail Website
Guest Editor
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China
Interests: antiviral drug; medicinal chemistry; drug design; new drug modalities
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Xinyong Liu

E-Mail Website
Guest Editor
Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan, China
Interests: innovative drug research; antiviral drug; drug design; medicinal chemistry; antigout drug
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Each year, viral infections including human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) cause millions of deaths, necessitating efforts to develop novel antivirals. During the last 40 years, we have witnessed unprecedented progress in the design and development of antiviral drugs. However, therapy to treat viral infections still remains one of the most substantial challenges in modern medicine because of the occurrence of resistance, latency, cytotoxicity, and so on. In addition, emerging and re-emerging pandemics continue to pose a major threat to human health, as is the case in the ongoing COVID-19 pandemic. The international scientific community is struggling to find new agents capable of combating the SARS-CoV-2 virus.

As is well known, target-guided drug design is a powerful approach to developing antiviral agents specifically tailored to a target. The elucidation and visualization of the three-dimensional structure of virus-related proteins has provided valuable insights into their molecular functions and allowed more powerful and reliable target-based design strategies.

In this Special Issue, recent endeavors and achievements in the field of antiviral drug research will be primarily outlined. Future directions and perspectives on target-guided antiviral drug discovery and associated challenges are also discussed.

Prof. Dr. Peng Zhan
Prof. Dr. Xinyong Liu
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • antiviral drug;
  • drug design;
  • medicinal chemistry;
  • innovative drug research;
  • drug resistance.

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Published Papers (6 papers)

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Research

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25 pages, 3292 KiB  
Article
Design, Synthesis, Biological Evaluation, and Molecular Dynamics Simulation of Influenza Polymerase PB2 Inhibitors
by Xinhong Li, Yijie Xu, Wei Li, Jinjing Che, Xu Zhao, Ruyuan Cao, Xingzhou Li and Song Li
Molecules 2023, 28(4), 1849; https://doi.org/10.3390/molecules28041849 - 15 Feb 2023
Cited by 5 | Viewed by 2391
Abstract
The PB2 subunit of the influenza RNA-dependent RNA polymerase (RdRp) has been identified as a promising target for the treatment of influenza. To expand the chemical space of the known influenza polymerase PB2 inhibitor–pimodivir (formerly VX-787) and improve its pharmacokinetic profile, two pimodivir [...] Read more.
The PB2 subunit of the influenza RNA-dependent RNA polymerase (RdRp) has been identified as a promising target for the treatment of influenza. To expand the chemical space of the known influenza polymerase PB2 inhibitor–pimodivir (formerly VX-787) and improve its pharmacokinetic profile, two pimodivir analogs containing 2,3-dihydro-imidazopyridine fragment (comp. I and comp. II) were designed, synthesized, and evaluated for anti-influenza virus activity. In the cytopathic effect (CPE) inhibition assay, comp. I and comp. II showed IC50 values of 0.07 and 0.09 μM for A/Puerto Rico/8/34 (H1N1) and 0.04 and 0.07 μM for A/Hong Kong/8/68 (H3N2), respectively. Protein-binding affinity assay results showed a concentration-dependent association and dissociation pattern, with KD values of 1.398 and 1.670 μM, respectively. In vitro metabolic stability assays showed that comp. I and comp. II exhibited good stability to liver microsomes and considerably less sensitivity to aldehyde oxidase compared to pimodivir. The binding modes of comp. I and comp. II were similar to those of VX-787; however, comp. I and comp. II had lower structural adaptability to PB2 than VX-787. Our results provide helpful information regarding the structure–activity relationship for the design of novel PB2 inhibitors and a reference for the development of drugs containing 2,3-dihydro-imidazopyridine fragments. Full article
(This article belongs to the Special Issue Design, Synthesis and Bioactivity Evaluation of Target-Based Antiviral Drugs)
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21 pages, 9058 KiB  
Article
Design, Synthesis, and Biological Evaluation of Benzimidazole Derivatives as Potential Lassa Virus Inhibitors
by Jinwei Chen, Likun Xu, Baogang Wang, Dongna Zhang, Liangliang Zhao, Zhuchun Bei and Yabin Song
Molecules 2023, 28(4), 1579; https://doi.org/10.3390/molecules28041579 - 7 Feb 2023
Cited by 8 | Viewed by 2104
Abstract
The Lassa virus (LASV) causes Lassa fever, a highly infectious and lethal agent of acute viral hemorrhagic fever. At present, there are still no effective treatments available, creating an urgent need to develop novel therapeutics. Some benzimidazole compounds targeting the arenavirus envelope glycoprotein [...] Read more.
The Lassa virus (LASV) causes Lassa fever, a highly infectious and lethal agent of acute viral hemorrhagic fever. At present, there are still no effective treatments available, creating an urgent need to develop novel therapeutics. Some benzimidazole compounds targeting the arenavirus envelope glycoprotein complex (GPC) are promising inhibitors of LASV. In this study, we synthesized two series of LASV inhibitors based on the benzimidazole structure. Lentiviral pseudotypes bearing the LASV GPC were established to identify virus entry inhibitors. Surface plasmon resonance (SPR) was further used to verify the binding activities of the potential compounds. Compounds 7d−Z, 7h−Z, 13c, 13d, and 13f showed relatively excellent antiviral activities with IC50 values ranging from 7.58 to 15.46 nM and their SI values above 1251. These five representative compounds exhibited stronger binding affinity with low equilibrium dissociation constants (KD < 8.25 × 10−7 M) in SPR study. The compound 7h−Z displayed the most potent antiviral activity (IC50 = 7.58 nM) with a relatively high SI value (2496), which could be further studied as a lead compound. The structure–activity relationship indicated that the compounds with lipophilic and spatially larger substituents might possess higher antiviral activity and a much larger safety margin. This study will provide some good guidance for the development of highly active compounds with a novel skeleton against LASV. Full article
(This article belongs to the Special Issue Design, Synthesis and Bioactivity Evaluation of Target-Based Antiviral Drugs)
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27 pages, 4021 KiB  
Article
The Development of Pharmacophore Models for the Search of New Natural Inhibitors of SARS-CoV-2 Spike RBD–ACE2 Binding Interface
by Valentin A. Semenov and Leonid B. Krivdin
Molecules 2022, 27(24), 8938; https://doi.org/10.3390/molecules27248938 - 15 Dec 2022
Viewed by 2002
Abstract
To date, some succeeding variants of SARS-CoV-2 have become more contagious. This virus is known to enter human cells by binding the receptor-binding domain (RBD) of spike protein with the angiotensin-converting enzyme 2 (ACE2), the latter being a membrane protein that regulates the [...] Read more.
To date, some succeeding variants of SARS-CoV-2 have become more contagious. This virus is known to enter human cells by binding the receptor-binding domain (RBD) of spike protein with the angiotensin-converting enzyme 2 (ACE2), the latter being a membrane protein that regulates the renin–angiotensin system. Since the host cell receptor plays a critical role in viral entry, inhibition of the RBD–ACE2 complex is a promising strategy for preventing COVID-19 infection. In the present communication, we propose and utilize an approach based on the generation of a complex of pharmacophore models and subsequent Induced Fit Docking (IFD) to identify potential inhibitors of the main binding sites of the Omicron SARS-CoV-2 RBD(S1)–ACE2 complex (PDB ID: 7T9L) among a number of natural products of various types and origins. Several natural compounds have been found to provide a high affinity for the receptor of interest. It is expected that the present results will stimulate further research aimed at the development of specialized drugs against this virus. Full article
(This article belongs to the Special Issue Design, Synthesis and Bioactivity Evaluation of Target-Based Antiviral Drugs)
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14 pages, 4031 KiB  
Article
Identification of Boronate-Containing Diarylpyrimidine Derivatives as Novel HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors
by Da Feng, Hao Lin, Liyang Jiang, Zhao Wang, Yanying Sun, Zhongxia Zhou, Erik De Clercq, Christophe Pannecouque, Dongwei Kang, Peng Zhan and Xinyong Liu
Molecules 2022, 27(21), 7538; https://doi.org/10.3390/molecules27217538 - 3 Nov 2022
Cited by 3 | Viewed by 1852
Abstract
In this study, privileged boronic acid ester was introduced into the right wing of etravirine (ETR) to obtain a series of novel boronate-containing derivatives. These newly synthesized derivatives were evaluated for their anti-HIV potency in MT-4 cells using the MTT method, and their [...] Read more.
In this study, privileged boronic acid ester was introduced into the right wing of etravirine (ETR) to obtain a series of novel boronate-containing derivatives. These newly synthesized derivatives were evaluated for their anti-HIV potency in MT-4 cells using the MTT method, and their inhibitory activity to HIV-1 reverse transcriptase (RT) was assayed by the ELISA method. Most of the synthesized compounds displayed promising antiviral activity against the wild-type and a wide range of HIV-1 mutant strains. In particular, 4a exhibited the most potent activity against the wild-type and a panel of single mutations (L100I, K103N, Y181C, and E138K) with EC50 values ranging from 0.005 to 0.648 μM, which were much superior to those of nevirapine (EC50 = 0.151 μM). Moreover, 4b turned out to be an effective inhibitor against the double-mutant strains F227L + V106A and RES056 with EC50 values of 3.21 and 2.30 μM, respectively. RT inhibition activity and molecular docking were also investigated. Full article
(This article belongs to the Special Issue Design, Synthesis and Bioactivity Evaluation of Target-Based Antiviral Drugs)
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8 pages, 1640 KiB  
Article
Doxycycline Interferes with Zika Virus Serine Protease and Inhibits Virus Replication in Human Skin Fibroblasts
by Teow Chong Teoh, Sawsam J. Al-Harbi, Ammar Yasir Abdulrahman and Hussin A. Rothan
Molecules 2021, 26(14), 4321; https://doi.org/10.3390/molecules26144321 - 16 Jul 2021
Cited by 9 | Viewed by 2774
Abstract
Zika virus (ZIKV) represents a re-emerging threat to global health due to its association with congenital birth defects. ZIKV NS2B-NS3 protease is crucial for virus replication by cleaving viral polyprotein at various junctions to release viral proteins and cause cytotoxic effects in ZIKV-infected [...] Read more.
Zika virus (ZIKV) represents a re-emerging threat to global health due to its association with congenital birth defects. ZIKV NS2B-NS3 protease is crucial for virus replication by cleaving viral polyprotein at various junctions to release viral proteins and cause cytotoxic effects in ZIKV-infected cells. This study characterized the inhibitory effects of doxycycline against ZIKV NS2B-NS3 protease and viral replication in human skin cells. The in silico data showed that doxycycline binds to the active site of ZIKV protease at a low docking energy (−7.8 Kcal/mol) via four hydrogen bonds with the protease residues TYR1130, SER1135, GLY1151, and ASP83. Doxycycline efficiently inhibited viral NS2B-NS3 protease at average human temperature (37 °C) and human temperature with a high fever during virus infection (40 °C). Interestingly, doxycycline showed a higher inhibitory effect at 40 °C (IC50 = 5.3 µM) compared to 37 °C (9.9 µM). The virus replication was considerably reduced by increasing the concentration of doxycycline. An approximately 50% reduction in virus replication was observed at 20 µM of doxycycline. Treatment with 20 µM of doxycycline reduced the cytopathic effects (CPE), and the 40 µM of doxycycline almost eliminated the CPE of human skin cells. This study showed that doxycycline binds to the ZIKV protease and inhibits its catalytic activity at a low micro-molecular concentration range. Treatment of human skin fibroblast with doxycycline eliminated ZIKV infection and protected the cells against the cytopathic effects of the infection. Full article
(This article belongs to the Special Issue Design, Synthesis and Bioactivity Evaluation of Target-Based Antiviral Drugs)
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19 pages, 4887 KiB  
Review
Current Progress in the Development of Hepatitis B Virus Capsid Assembly Modulators: Chemical Structure, Mode-of-Action and Efficacy
by Hyejin Kim, Chunkyu Ko, Joo-Youn Lee and Meehyein Kim
Molecules 2021, 26(24), 7420; https://doi.org/10.3390/molecules26247420 - 7 Dec 2021
Cited by 23 | Viewed by 5176
Abstract
Hepatitis B virus (HBV) is a major causative agent of human hepatitis. Its viral genome comprises partially double-stranded DNA, which is complexed with viral polymerase within an icosahedral capsid consisting of a dimeric core protein. Here, we describe the effects of capsid assembly [...] Read more.
Hepatitis B virus (HBV) is a major causative agent of human hepatitis. Its viral genome comprises partially double-stranded DNA, which is complexed with viral polymerase within an icosahedral capsid consisting of a dimeric core protein. Here, we describe the effects of capsid assembly modulators (CAMs) on the geometric or kinetic disruption of capsid construction and the virus life cycle. We highlight classical, early-generation CAMs such as heteroaryldihydropyrimidines, phenylpropenamides or sulfamoylbenzamides, and focus on the chemical structure and antiviral efficacy of recently identified non-classical CAMs, which consist of carboxamides, aryl ureas, bithiazoles, hydrazones, benzylpyridazinones, pyrimidines, quinolines, dyes, and antimicrobial compounds. We summarize the therapeutic efficacy of four representative classical compounds with data from clinical phase 1 studies in chronic HBV patients. Most of these compounds are in phase 2 trials, either as monotherapy or in combination with approved nucleos(t)ides drugs or other immunostimulatory molecules. As followers of the early CAMs, the therapeutic efficacy of several non-classical CAMs has been evaluated in humanized mouse models of HBV infection. It is expected that these next-generation HBV CAMs will be promising candidates for a series of extended human clinical trials. Full article
(This article belongs to the Special Issue Design, Synthesis and Bioactivity Evaluation of Target-Based Antiviral Drugs)
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