In Vitro Combinatorial Activity of Direct Acting Antivirals and Monoclonal Antibodies against the Ancestral B.1 and BQ.1.1 SARS-CoV-2 Viral Variants DOI Open Access
Lia Fiaschi,

Camilla Biba,

Ilenia Varasi

et al.

Published: Jan. 3, 2024

Combination antiviral therapy may be helpful in the treatment of SARS-CoV-2 infection, however no clinical trial data are available and combined use direct acting antivirals (DAA) monoclonal antibodies (mAb) has been reported only anecdotally. To assess cooperative effects dual drug combinations vitro, we used a VERO E6 cell based vitro system with ancestral B.1 or highly divergent BQ.1.1 virus to test pairwise licensed DAA, including nirmatrelvir (NRM), remdesivir (RDV) active metabolite molnupiravir (EIDD-1931) as well combination RDV four mAbs (sotrovimab, bebtelovimab, cilgavimab, tixagevimab; tested susceptible virus). According SynergyFinder 3.0 summary weighted scores, all had an additive effect. Within DAA/DAA combinations, paired scores variants were comparable. In post-hoc analysis weighting synergy by concentrations, several cases synergistic detected at specific both for RDV/mAb combinations. This was supported confirmation experiments showing more than linear shift effective concentration (IC50) increasing concentrations companion drug, although effect prominent but minimal null These results support which should further investigated animal models before introduction into clinic.

Language: Английский

Computational screening of potential bromodomain-containing protein 2 inhibitors for blocking SARS-CoV-2 infection through pharmacophore modeling, molecular docking and molecular dynamics simulation DOI Creative Commons
Shaohua Xu,

Huicheng Yuan,

Ling Li

et al.

Arabian Journal of Chemistry, Journal Year: 2023, Volume and Issue: 17(1), P. 105365 - 105365

Published: Oct. 20, 2023

Recently, human bromodomain-containing protein 2 (BRD2) has been reported as a potential drug target in host cells to combat SARS-CoV-2 well treat COVID-19. In this study, we aimed screen BRD2 inhibitors anti- agents through computational approach. A pharmacophore model was generated with crystal structure of complex RVX208 using ZINCPharmer server, and 10,842 compounds were screened from ZINC15 database against the model. Next, 102 exhibited more affinity than control compound (RVX208) molecular docking. The top five hits (ZINC20417563, ZINC12322175, ZINC12391479, ZINC13098192, ZINC20407881), which showed docking -10, -9.9, -9.8, -9.7 kcal/mol, respectively, subjected 100ns dynamics simulation evaluate stability docked complexes their interaction mechanisms. appropriate these displayed, found be closely adhered binding site based on global analysis RMSD, RMSF, Rg, SASA, DSSP H-bond. essential principal component analysis, dynamic cross-correlation matrix, free energy landscape remained stable conformation throughout simulation. addition, pharmacokinetic ADMET properties could candidates. findings study may contribute further examinational validation rational design novel anti-SARS-CoV-2 agents.

Language: Английский

Citations

14
Bioluminescence imaging reveals enhanced SARS-CoV-2 clearance in mice with combinatorial regimens DOI Creative Commons
Irfan Ullah, Fanny Escudié, Ivan Scandale

et al.

iScience, Journal Year: 2024, Volume and Issue: 27(3), P. 109049 - 109049

Published: Jan. 30, 2024

Language: Английский

Citations

6
Seven classes of antiviral agents DOI Creative Commons
Aleksandr Ianevski, Shahzaib Ahmad,

Kraipit Anunnitipat

et al.

Cellular and Molecular Life Sciences, Journal Year: 2022, Volume and Issue: 79(12)

Published: Nov. 27, 2022

The viral epidemics and pandemics have stimulated the development of known discovery novel antiviral agents. About a hundred mono- combination drugs been already approved, whereas thousands are in development. Here, we briefly reviewed 7 classes agents: neutralizing antibodies, recombinant soluble human receptors, CRISPR/Cas systems, interferons, peptides, nucleic acid polymers, small molecules. Interferons some molecules alone or combinations possess broad-spectrum activity, which could be beneficial for treatment emerging re-emerging infections.

Language: Английский

Citations

18
Two-way pharmacodynamic modeling of drug combinations and its application to pairs of repurposed Ebola and SARS-CoV-2 agents DOI Creative Commons
Shuang Xu, Shadisadat Esmaeili, E. Fabián Cardozo-Ojeda

et al.

Antimicrobial Agents and Chemotherapy, Journal Year: 2024, Volume and Issue: 68(4)

Published: March 12, 2024

ABSTRACT Existing pharmacodynamic (PD) mathematical models for drug combinations discriminate antagonistic, additive, multiplicative, and synergistic effects, but fail to consider how concentration-dependent interaction effects may vary across an entire dose-response matrix. We developed a two-way (TWPD) model capture the PD of two-drug combinations. TWPD captures interactions between upstream downstream drugs that act on different stages viral replication, by quantifying efficacy parameters. applied previously published in vitro matrixes repurposed potential anti-Ebola anti-SARS-CoV-2 pairs. Depending pairing, recapitulated combined efficacies as or more accurately than existing can be used infer at untested concentrations. fits data slightly better one direction all pairs, meaning we tentatively drug. Based its high accuracy, could concert with PK estimate therapeutic pairs vivo .

Language: Английский

Citations

3
Gemcitabine combined with baicalein exerts antiviral activity against PEDV by inhibiting the entry and replication phases DOI Creative Commons

Yingge Zheng,

Yanfei Zhang,

Fangying Xiong

et al.

Animal Diseases, Journal Year: 2025, Volume and Issue: 5(1)

Published: Feb. 6, 2025

Abstract Cocktail therapy significantly reduces the development of resistance to individual medications due viral mutations. However, for effective inhibition a particular virus, customized approach combination pharmacotherapy may be essential. Porcine epidemic diarrhea virus (PEDV) is member Coronaviridae family, whose genome consists single strand positive-sense RNA and has evolved into multiple lineages with no available drugs in clinical practice. In this study, we found that nucleoside analog gemcitabine decreased titer PEDV, median concentration (EC 50 ) 3.12 μM, thereby inhibiting replication. The natural product baicalein acts by targeting early entry stage directly inactivates an EC 5.02 μM. A notable synergistic effect was observed 1 μM 1.5 baicalein. This study demonstrated strategic use drug both replication phases PEDV lifecycle can effectively inhibit proliferation.

Language: Английский

Citations

0
Host-targeted antivirals against SARS-CoV-2 in clinical development - prospect or disappointment? DOI Creative Commons
André Schreiber, Stephan Ludwig

Antiviral Research, Journal Year: 2025, Volume and Issue: 235, P. 106101 - 106101

Published: Feb. 7, 2025

The global response to the COVID-19 pandemic, caused by novel SARS-CoV-2 virus, has seen an unprecedented increase in development of antiviral therapies. Traditional strategies have primarily focused on direct-acting antivirals (DAAs), which specifically target viral components. In recent years, increasing attention was given alternative approach aiming exploit host cellular pathways or immune responses inhibit replication, led so-called host-targeted (HTAs). emergence and promoted a boost this field. Numerous HTAs been tested demonstrated their potential against through vitro vivo studies. However, striking contrast, only limited number successfully progressed advanced clinical trial phases (2-4), even less entered practice. This review aims explore current landscape targeting that reached phase 2-4 trials. Additionally, it will challenges faced gaining regulatory approval market availability.

Language: Английский

Citations

0
Inhaled Dry Powder of Antiviral Agents: A Promising Approach to Treating Respiratory Viral Pathogens DOI Creative Commons
Tushar Saha,

Zia Uddin Masum,

Anik Naha Biswas

et al.

Viruses, Journal Year: 2025, Volume and Issue: 17(2), P. 252 - 252

Published: Feb. 12, 2025

Inhaled dry powder formulations of antiviral agents represent a novel and potentially transformative approach to managing respiratory viral infections. Traditional therapies in the form tablets or capsules often face limitations terms therapeutic activity, systemic side effects, delayed onset action. Dry inhalers (DPIs) provide targeted delivery system, ensuring direct administration antivirals infection site, tract, which enhance efficacy minimize exposure. This review explores current state inhaled agents, their advantages over traditional routes, specific under development. We discuss benefits delivery, such as improved drug deposition lungs reduced alongside considerations related formulation preparation. In addition, we summarize developed (published marketed) powders agents.

Language: Английский

Citations

0
Influenza H5Nx Viruses are susceptible to MEK1/2 Inhibition by zapnometinib DOI Creative Commons
André Schreiber,

Nicole Oberberg,

Benjamin Ambrosy

et al.

Emerging Microbes & Infections, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 20, 2025

Highly pathogenic avian influenza A viruses (HPAIV) pose a significant threat to both animal and human health. These have the potential cause severe respiratory systemic infections in birds several mammalian species. The recent global outbreak of H5N1 clade 2.3.4.4b spread wild domestic is now considered be panzoonosis. Spillover events dairy cattle farms U.S. highlighted urgent need for effective antiviral therapies, especially view infections. This study investigates selective MEK1/2 inhibitor zapnometinib (ZMN) as agent against HPAIVs. Our vitro experiments demonstrate that ZMN significantly impairs viral replication across multiple HPAIV strains, including cell lines primary bronchial epithelial cells. mechanism action based on nuclear retention newly produced ribonucleoprotein complexes (vRNP), when MEK/ERK/RSK1 kinase cascade inhibited. We furthermore could show, not only acts standalone treatment but has synergistic used combination with direct acting antivirals like oseltamivir or baloxavir. Therefore, offers promising strategy future development.

Language: Английский

Citations

0
Broad-spectrum Antiviral Ferruginol Analog Affects the Viral Proteins Translation and Actin Remodeling During Dengue Virus Infection DOI Creative Commons
Vicky C. Roa-Linares, Liliana Betancur‐Galvis, Miguel A. González-Cardenete

et al.

Antiviral Research, Journal Year: 2025, Volume and Issue: 237, P. 106139 - 106139

Published: March 4, 2025

Language: Английский

Citations

0
Advancing Viral Defense: Unravelling the Potential of Host-Directed Antivirals Against SARS-CoV-2 DOI Creative Commons
Zheng Yao Low, Siau Wui Chin, Sharifah Syed Hassan

et al.

Drugs and Drug Candidates, Journal Year: 2025, Volume and Issue: 4(2), P. 13 - 13

Published: March 28, 2025

The COVID-19 pandemic, driven by the high transmissibility and immune evasion caused SARS-CoV-2 its variants (e.g., Alpha, Delta, Omicron), has led to massive casualties worldwide. As of November 2024, International Committee on Taxonomy Viruses (ICTV) identified 14,690 viral species across 3522 genera. increasing infectious resistance FDA EMA-approved antivirals, such as 300-fold efficacy reduction in Nirmatrelvir against 3CLpro, highlight need for mutation-stable likewise targeting essential host proteins like kinases, heat shock proteins, lipid metabolism immunological pathway etc. Unlike direct-acting HDAs reduce risk conserved replication. proposal repurposing current FDA-approved drugs host-directed antiviral (HDA) approach is not new, Ouabain, a sodium-potassium ATPase inhibitor herpes simplex virus (HSV) Verapamil, calcium channel blocker influenza A (IAV), name few. Given colossal potential HDA exterminate infection, it been increasingly studied SARS-CoV-2. This review aims unravel interaction between viruses human hosts their successfully proposed provide insight into an alternative treatment rampant mutation benefits, limitations, protein-targeted therapies prospects are also covered this review.

Language: Английский

Citations

0