International Journal of Molecular Sciences

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4 pages, 190 KiB

Open AccessEditorial

Antiviral Drug Discovery

by Zhenzhen Zhou, Xinyong Liu and Dongwei Kang

Int. J. Mol. Sci. 2024, 25(13), 7413; https://doi.org/10.3390/ijms25137413 - 6 Jul 2024

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Abstract

A vast and painful price has been paid in the battle against viruses in global health [...] Full article

(This article belongs to the Special Issue Antiviral Drug Discovery)

Research

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12 pages, 4005 KiB

Open AccessArticle

Discovery of Novel Amino Acids (Analogues)-Substituted Thiophene[3,2-d]pyrimidine Derivatives as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: Design, Synthesis, and Biological Evaluation

by Zongji Zhuo, Zhao Wang, Lanlan Jing, Tao Zhang, Anchao Ge, Zhenzhen Zhou, Ying Liu, Xin Li, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Xinyong Liu and Dongwei Kang

Int. J. Mol. Sci. 2024, 25(16), 9028; https://doi.org/10.3390/ijms25169028 - 20 Aug 2024

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Abstract

Inspired by our previous work on the modification of diarylpyrimidine-typed non-nucleoside reverse transcriptase inhibitors (NNRTIs) and the reported crystallographic studies, a series of novel amino acids (analogues)-substituted thiophene[3,2-d]pyrimidine derivatives were designed and synthesized by targeting the solvent-exposed region of the NNRTI-binding [...] Read more.

Inspired by our previous work on the modification of diarylpyrimidine-typed non-nucleoside reverse transcriptase inhibitors (NNRTIs) and the reported crystallographic studies, a series of novel amino acids (analogues)-substituted thiophene[3,2-d]pyrimidine derivatives were designed and synthesized by targeting the solvent-exposed region of the NNRTI-binding pocket. The biological evaluation results showed that compound 5k was the most active inhibitor, exhibiting moderate-to-excellent potency against HIV-1 wild-type (WT) and a panel of NNRTI-resistant strains, with EC₅₀ values ranging from 0.042 μM to 7.530 μM. Of special note, 5k exhibited the most potent activity against single-mutant strains (K103N and E138K), with EC₅₀ values of 0.031 μM and 0.094 μM, being about 4.3-fold superior to EFV (EC₅₀ = 0.132 μM) and 1.9-fold superior to NVP (EC₅₀ = 0.181 μM), respectively. In addition, 5k demonstrated lower cytotoxicity (CC₅₀ = 27.9 μM) and higher selectivity index values. The HIV-1 reverse transcriptase (RT) inhibition assay was further performed to confirm their binding target. Moreover, preliminary structure–activity relationships (SARs) and molecular docking studies were also discussed in order to provide valuable insights for further structural optimizations. In summary, 5k turned out to be a promising NNRTI lead compound for further investigations of treatments for HIV-1 infections. Full article

(This article belongs to the Special Issue Antiviral Drug Discovery)

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22 pages, 2810 KiB

Open AccessArticle

Design and Synthesis of New GS-6207 Subtypes for Targeting HIV-1 Capsid Protein

by Thamina Akther, William M. McFadden, Huanchun Zhang, Karen A. Kirby, Stefan G. Sarafianos and Zhengqiang Wang

Int. J. Mol. Sci. 2024, 25(7), 3734; https://doi.org/10.3390/ijms25073734 - 27 Mar 2024

Cited by 2 | Viewed by 1841

Abstract

HIV-1 capsid protein (CA) is the molecular target of the recently FDA-approved long acting injectable (LAI) drug lenacapavir (GS-6207). The quick emergence of CA mutations resistant to GS-6207 necessitates the design and synthesis of novel sub-chemotypes. We have conducted the structure-based design of [...] Read more.

HIV-1 capsid protein (CA) is the molecular target of the recently FDA-approved long acting injectable (LAI) drug lenacapavir (GS-6207). The quick emergence of CA mutations resistant to GS-6207 necessitates the design and synthesis of novel sub-chemotypes. We have conducted the structure-based design of two new sub-chemotypes combining the scaffold of GS-6207 and the N-terminal cap of PF74 analogs, the other important CA-targeting chemotype. The design was validated via induced-fit molecular docking. More importantly, we have worked out a general synthetic route to allow the modular synthesis of novel GS-6207 subtypes. Significantly, the desired stereochemistry of the skeleton C² was confirmed via an X-ray crystal structure of the key synthetic intermediate 22a. Although the newly synthesized analogs did not show significant potency, our efforts herein will facilitate the future design and synthesis of novel subtypes with improved potency. Full article

(This article belongs to the Special Issue Antiviral Drug Discovery)

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21 pages, 10802 KiB

Open AccessArticle

Baicalin Protects Broilers against Avian Coronavirus Infection via Regulating Respiratory Tract Microbiota and Amino Acid Metabolism

by Haipeng Feng, Jingyan Zhang, Xuezhi Wang, Zhiting Guo, Lei Wang, Kang Zhang and Jianxi Li

Int. J. Mol. Sci. 2024, 25(4), 2109; https://doi.org/10.3390/ijms25042109 - 9 Feb 2024

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Abstract

An increasing amount of evidence indicates that Baicalin (Bai, a natural glycosyloxyflavone compound) exhibits an antiviral effect against avian viruses. However, it remains unclear if the antiviral effect of Bai against infectious bronchitis virus (IBV) is exerted indirectly by modulating respiratory tract microbiota [...] Read more.

An increasing amount of evidence indicates that Baicalin (Bai, a natural glycosyloxyflavone compound) exhibits an antiviral effect against avian viruses. However, it remains unclear if the antiviral effect of Bai against infectious bronchitis virus (IBV) is exerted indirectly by modulating respiratory tract microbiota and/or their metabolites. In this study, we investigated the protection efficacy of Bai in protecting cell cultures and broilers from IBV infection and assessed modulation of respiratory tract microbiota and metabolites during infection. Bai was administered orally to broilers by being mixed in with drinking water for seven days. Ultimately, broilers were challenged with live IBV. The results showed that Bai treatment reduced respiratory tract symptoms, improved weight gain, slowed histopathological damage, reduced virus loads and decreased pro-inflammation cytokines production. Western blot analysis demonstrated that Bai treatment significantly inhibited Toll-like receptor 7 (TLR7), myeloid differentiation factor 88 (MyD88) and nuclear factor kappa-B (NF-κB) expression both in cell culture and cells of the trachea. Bai treatment reversed respiratory tract microbiota dysbiosis, as shown by 16S rDNA sequencing in the group of broilers inoculated with IBV. Indeed, we observed a decrease in Proteobacteria abundance and an increase in Firmicutes abundance. Metabolomics results suggest that the pentose phosphate pathway, amino acid and nicotinamide metabolism are linked to the protection conferred by Bai against IBV infection. In conclusion, these results indicated that further assessment of anti-IBV strategies based on Bai would likely result in the development of antiviral molecule(s) which can be administered by being mixed with feed or water. Full article

(This article belongs to the Special Issue Antiviral Drug Discovery)

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21 pages, 3816 KiB

Open AccessArticle

AI-Driven De Novo Design and Molecular Modeling for Discovery of Small-Molecule Compounds as Potential Drug Candidates Targeting SARS-CoV-2 Main Protease

by Alexander M. Andrianov, Mikita A. Shuldau, Konstantin V. Furs, Artsemi M. Yushkevich and Alexander V. Tuzikov

Int. J. Mol. Sci. 2023, 24(9), 8083; https://doi.org/10.3390/ijms24098083 - 29 Apr 2023

Cited by 7 | Viewed by 2970

Abstract

Over the past three years, significant progress has been made in the development of novel promising drug candidates against COVID-19. However, SARS-CoV-2 mutations resulting in the emergence of new viral strains that can be resistant to the drugs used currently in the clinic [...] Read more.

Over the past three years, significant progress has been made in the development of novel promising drug candidates against COVID-19. However, SARS-CoV-2 mutations resulting in the emergence of new viral strains that can be resistant to the drugs used currently in the clinic necessitate the development of novel potent and broad therapeutic agents targeting different vulnerable spots of the viral proteins. In this study, two deep learning generative models were developed and used in combination with molecular modeling tools for de novo design of small molecule compounds that can inhibit the catalytic activity of SARS-CoV-2 main protease (Mpro), an enzyme critically important for mediating viral replication and transcription. As a result, the seven best scoring compounds that exhibited low values of binding free energy comparable with those calculated for two potent inhibitors of Mpro, via the same computational protocol, were selected as the most probable inhibitors of the enzyme catalytic site. In light of the data obtained, the identified compounds are assumed to present promising scaffolds for the development of new potent and broad-spectrum drugs inhibiting SARS-CoV-2 Mpro, an attractive therapeutic target for anti-COVID-19 agents. Full article

(This article belongs to the Special Issue Antiviral Drug Discovery)

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27 pages, 6003 KiB

Open AccessArticle

Comparing the Effects of Rocaglates on Energy Metabolism and Immune Modulation on Cells of the Human Immune System

by Susanne Schiffmann, Marina Henke, Michelle Seifert, Thomas Ulshöfer, Luise A. Roser, Francesca Magari, Hans-Guido Wendel, Arnold Grünweller and Michael J. Parnham

Int. J. Mol. Sci. 2023, 24(6), 5872; https://doi.org/10.3390/ijms24065872 - 20 Mar 2023

Cited by 4 | Viewed by 2487

Abstract

A promising new approach to broad spectrum antiviral drugs is the inhibition of the eukaryotic translation initiation factor 4A (elF4A), a DEAD-box RNA helicase that effectively reduces the replication of several pathogenic virus types. Beside the antipathogenic effect, modulation of a host enzyme [...] Read more.

A promising new approach to broad spectrum antiviral drugs is the inhibition of the eukaryotic translation initiation factor 4A (elF4A), a DEAD-box RNA helicase that effectively reduces the replication of several pathogenic virus types. Beside the antipathogenic effect, modulation of a host enzyme activity could also have an impact on the immune system. Therefore, we performed a comprehensive study on the influence of elF4A inhibition with natural and synthetic rocaglates on various immune cells. The effect of the rocaglates zotatifin, silvestrol and CR-31-B (−), as well as the nonactive enantiomer CR-31-B (+), on the expression of surface markers, release of cytokines, proliferation, inflammatory mediators and metabolic activity in primary human monocyte-derived macrophages (MdMs), monocyte-derived dendritic cells (MdDCs), T cells and B cells was assessed. The inhibition of elF4A reduced the inflammatory potential and energy metabolism of M1 MdMs, whereas in M2 MdMs, drug-specific and less target-specific effects were observed. Rocaglate treatment also reduced the inflammatory potential of activated MdDCs by altering cytokine release. In T cells, the inhibition of elF4A impaired their activation by reducing the proliferation rate, expression of CD25 and cytokine release. The inhibition of elF4A further reduced B-cell proliferation, plasma cell formation and the release of immune globulins. In conclusion, the inhibition of the elF4A RNA helicase with rocaglates suppressed the function of M1 MdMs, MdDCs, T cells and B cells. This suggests that rocaglates, while inhibiting viral replication, may also suppress bystander tissue injury by the host immune system. Thus, dosing of rocaglates would need to be adjusted to prevent excessive immune suppression without reducing their antiviral activity. Full article

(This article belongs to the Special Issue Antiviral Drug Discovery)

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16 pages, 13667 KiB

Open AccessArticle

Antiviral Effect of Ginsenosides rk1 against Influenza a Virus Infection by Targeting the Hemagglutinin 1-Mediated Virus Attachment

by Xia Yang, Hailiang Sun, Zhening Zhang, Weixin Ou, Fengxiang Xu, Ling Luo, Yahong Liu, Weisan Chen and Jianxin Chen

Int. J. Mol. Sci. 2023, 24(5), 4967; https://doi.org/10.3390/ijms24054967 - 4 Mar 2023

Cited by 3 | Viewed by 2448

Abstract

Influenza A virus (IAV) infections have been a serious hazard to public health everywhere. With the growing concern of drug-resistant IAV strains, there is an urgent need for novel anti-IAV medications, especially those with alternative mechanisms of action. Hemagglutinin (HA), an IAV glycoprotein, [...] Read more.

Influenza A virus (IAV) infections have been a serious hazard to public health everywhere. With the growing concern of drug-resistant IAV strains, there is an urgent need for novel anti-IAV medications, especially those with alternative mechanisms of action. Hemagglutinin (HA), an IAV glycoprotein, plays critical roles in the early stage of virus infection, including receptor binding and membrane fusion, making it a good target for developing anti-IAV drugs. Panax ginseng is a widely used herb in traditional medicine with extensive biological effects in various disease models, and its extract was reported to show protection in IAV-infected mice. However, the main effective anti-IAV constituents in panax ginseng remain unclear. Here, we report that ginsenoside rk1 (G-rk1) and G-rg5, out of the 23 screened ginsenosides, exhibit significant antiviral effects against 3 different IAV subtypes (H1N1, H5N1, and H3N2) in vitro. Mechanistically, G-rk1 blocked IAV binding to sialic acid in a hemagglutination inhibition (HAI) assay and an indirect ELISA assay; more importantly, we showed that G-rk1 interacted with HA1 in a dose-dependent manner in a surface plasmon resonance (SPR) analysis. Furthermore, G-rk1 treatment by intranasal inoculation effectively reduced the weight loss and mortality of mice challenged with a lethal dose of influenza virus A/Puerto Rico/8/34 (PR8). In conclusion, our findings reveal for the first time that G-rk1 possesses potent anti-IAV effects in vitro and in vivo. We have also identified and characterized with a direct binding assay a novel ginseng-derived IAV HA1 inhibitor for the first time, which could present potential approaches to prevent and treat IAV infections. Full article

(This article belongs to the Special Issue Antiviral Drug Discovery)

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12 pages, 4647 KiB

Open AccessArticle

Covalently Targeted Highly Conserved Tyr318 to Improve the Drug Resistance Profiles of HIV-1 NNRTIs: A Proof-of-Concept Study

by Zhenzhen Zhou, Bairu Meng, Jiaqi An, Fabao Zhao, Yanying Sun, Dan Zeng, Wenna Wang, Shenghua Gao, Yu Xia, Caiyun Dun, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Dongwei Kang and Xinyong Liu

Int. J. Mol. Sci. 2023, 24(2), 1215; https://doi.org/10.3390/ijms24021215 - 7 Jan 2023

Cited by 4 | Viewed by 2201

Abstract

This study presents proof of concept for designing a novel HIV-1 covalent inhibitor targeting the highly conserved Tyr318 in the HIV-1 non-nucleoside reverse transcriptase inhibitors binding pocket to improve the drug resistance profiles. The target inhibitor ZA-2 with a fluorosulfate warhead in the [...] Read more.

This study presents proof of concept for designing a novel HIV-1 covalent inhibitor targeting the highly conserved Tyr318 in the HIV-1 non-nucleoside reverse transcriptase inhibitors binding pocket to improve the drug resistance profiles. The target inhibitor ZA-2 with a fluorosulfate warhead in the structure was found to be a potent inhibitor (EC₅₀ = 11–246 nM) against HIV-1 IIIB and a panel of NNRTIs-resistant strains, being far superior to those of NVP and EFV. Moreover, ZA-2 was demonstrated with lower cytotoxicity (CC₅₀ = 125 µM). In the reverse transcriptase inhibitory assay, ZA-2 exhibited an IC₅₀ value of 0.057 µM with the ELISA method, and the MALDI-TOF MS data demonstrated the covalent binding mode of ZA-2 with the enzyme. Additionally, the molecular simulations have also demonstrated that compounds can form covalent binding to the Tyr318. Full article

(This article belongs to the Special Issue Antiviral Drug Discovery)

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Review

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17 pages, 960 KiB

Open AccessReview

Assessing the Potential Contribution of In Silico Studies in Discovering Drug Candidates That Interact with Various SARS-CoV-2 Receptors

by Aganze Gloire-Aimé Mushebenge, Samuel Chima Ugbaja, Nonkululeko Avril Mbatha, Rene B. Khan and Hezekiel M. Kumalo

Int. J. Mol. Sci. 2023, 24(21), 15518; https://doi.org/10.3390/ijms242115518 - 24 Oct 2023

Cited by 7 | Viewed by 3182

Abstract

The COVID-19 pandemic has spurred intense research efforts to identify effective treatments for SARS-CoV-2. In silico studies have emerged as a powerful tool in the drug discovery process, particularly in the search for drug candidates that interact with various SARS-CoV-2 receptors. These studies [...] Read more.

The COVID-19 pandemic has spurred intense research efforts to identify effective treatments for SARS-CoV-2. In silico studies have emerged as a powerful tool in the drug discovery process, particularly in the search for drug candidates that interact with various SARS-CoV-2 receptors. These studies involve the use of computer simulations and computational algorithms to predict the potential interaction of drug candidates with target receptors. The primary receptors targeted by drug candidates include the RNA polymerase, main protease, spike protein, ACE2 receptor, and transmembrane protease serine 2 (TMPRSS2). In silico studies have identified several promising drug candidates, including Remdesivir, Favipiravir, Ribavirin, Ivermectin, Lopinavir/Ritonavir, and Camostat Mesylate, among others. The use of in silico studies offers several advantages, including the ability to screen a large number of drug candidates in a relatively short amount of time, thereby reducing the time and cost involved in traditional drug discovery methods. Additionally, in silico studies allow for the prediction of the binding affinity of the drug candidates to target receptors, providing insight into their potential efficacy. This study is aimed at assessing the useful contributions of the application of computational instruments in the discovery of receptors targeted in SARS-CoV-2. It further highlights some identified advantages and limitations of these studies, thereby revealing some complementary experimental validation to ensure the efficacy and safety of identified drug candidates. Full article

(This article belongs to the Special Issue Antiviral Drug Discovery)

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