Antiviral research最新文献

{"title":"Evaluation of pharmacokinetics of Tenofovir Alafenamide (TAF) and Tenofovir Disoproxil (TDF) in pregnant and postpartum women in South Africa: PrEP-PP PK study","authors":"Dvora Joseph Davey ,&nbsp;Sumaya Dadan ,&nbsp;Kalisha Bheemraj ,&nbsp;Catriona Waitt ,&nbsp;Saye Khoo ,&nbsp;Landon Myer ,&nbsp;Lubbe Wiesner ,&nbsp;Laura Else ,&nbsp;Beth Thompson ,&nbsp;Sandra Castel ,&nbsp;Nafisa Wara ,&nbsp;Peter L. Anderson ,&nbsp;Catherine Orrell","doi":"10.1016/j.antiviral.2024.106014","DOIUrl":"10.1016/j.antiviral.2024.106014","url":null,"abstract":"<div><h3>Background</h3><div>There are few data on tenofovir-diphosphate (TFV-DP) concentrations in pregnant and postpartum women on Tenofovir Disoproxil Fumarate-Emtricitabine (TDF-FTC) or Tenofovir Alafenamide-Emtricitabine (TAF-FTC).</div></div><div><h3>Methods</h3><div>Eligible pregnant women were randomized to TDF-FTC or TAF-FTC and followed for 16 weeks (8-weeks pregnant, 8-weeks postpartum) with weekly collection of dried blood spot (DBS) and 4-weekly peripheral blood mononuclear cells (PBMC). PrEP dosing was observed daily via asynchronous videos sent via cell phone. We report geometric means (GM) and their ratios (GMR) with 95% confidence intervals (CIs) for TFV-DP in PBMC and DBS from pregnancy and postpartum.</div></div><div><h3>Results</h3><div>We enrolled N = 39 participants (n = 19 TDF-FTC, n = 20 TAF-FTC): median age was 28 years (IQR:25–34); median gestational age was 24-weeks (IQR:21–28). For TDF-FTC, TFV-DP DBS concentrations at 8-weeks did not differ significantly between pregnancy (GM: 675; 95%CI:537–849) and postpartum (GM: 583; 95%CI:471–722; GMR-TDF = 1.16; 95%CI:0.74–1.80). For TAF-FTC, TFV-DP DBS concentrations at 8-weeks were 44% higher in postpartum (GM: 1199; 95%CI:929–1549) versus pregnancy (GM: 832; 95%CI:751–922; GMR-TAF = 1.44; 95% CI: 1.01–2.06). In PBMC analysis of TDF-FTC, 8-week median TFV-DP (pmol/10^6 cell) was 71 (IQR 44–112) in pregnancy and 73 (IQR 50–102) in postpartum (GMR = 1.04; 95%CI:0.44–2.44). In TAF-FTC, median PBMC at 8-weeks was 580 (IQR:341–985) in pregnancy and 666 (IQR:396–1123) in postpartum (GMR = 1.15; 95%CI:0.30–2.49).</div></div><div><h3>Conclusion</h3><div>TFV-DP concentrations were overall lower during pregnancy than postpartum for TAF-FTC. We found high concentrations of TFV-DP in PBMC in pregnancy and postpartum on TAF-FTC, suggesting PrEP efficacy is maintained. Efficacy and safety studies are warranted to evaluate TAF-FTC for PrEP in pregnant and postpartum women.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"231 ","pages":"Article 106014"},"PeriodicalIF":4.5,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142340060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Large-scale deep learning identifies the antiviral potential of PKI-179 and MTI-31 against coronaviruses","authors":"Demi van der Horst ,&nbsp;Madalina E. Carter-Timofte ,&nbsp;Adeline Danneels ,&nbsp;Leandro Silva da Costa ,&nbsp;Naziia Kurmasheva ,&nbsp;Anne L. Thielke ,&nbsp;Anne Louise Hansen ,&nbsp;Vladimir Chorošajev ,&nbsp;Christian K. Holm ,&nbsp;Sandrine Belouzard ,&nbsp;Ivan de Weber ,&nbsp;Cedric Beny ,&nbsp;David Olagnier","doi":"10.1016/j.antiviral.2024.106012","DOIUrl":"10.1016/j.antiviral.2024.106012","url":null,"abstract":"<div><div>Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to the global pandemic of Coronavirus Disease (2019) (COVID-19), underscoring the urgency for effective antiviral drugs. Despite the development of different vaccination strategies, the search for specific antiviral compounds remains crucial. Here, we combine machine learning (ML) techniques with <em>in vitro</em> validation to efficiently identify potential antiviral compounds. We overcome the limited amount of SARS-CoV-2 data available for ML using various techniques, supplemented with data from diverse biomedical assays, which enables end-to-end training of a deep neural network architecture. We use its predictions to identify and prioritize compounds for <em>in vitro</em> testing. Two top-hit compounds, PKI-179 and MTI-31, originally identified as Pi3K-mTORC1/2 pathway inhibitors, exhibit significant antiviral activity against SARS-CoV-2 at low micromolar doses. Notably, both compounds outperform the well-known mTOR inhibitor rapamycin. Furthermore, PKI-179 and MTI-31 demonstrate broad-spectrum antiviral activity against SARS-CoV-2 variants of concern and other coronaviruses. In a physiologically relevant model, both compounds show antiviral effects in primary human airway epithelial (HAE) cultures derived from healthy donors cultured in an air-liquid interface (ALI). This study highlights the potential of ML combined with <em>in vitro</em> testing to expedite drug discovery, emphasizing the adaptability of AI-driven approaches across different viruses, thereby contributing to pandemic preparedness.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"231 ","pages":"Article 106012"},"PeriodicalIF":4.5,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142327856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dendritic cell-based biomimetic nanoparticles for foot-and-mouth disease induce robust cellular immunity","authors":"Zhan Gao ,&nbsp;Xiaoqing Liu ,&nbsp;Yao Lei ,&nbsp;Junjun Shao ,&nbsp;Guanglei Zhang ,&nbsp;Zhuo Hou ,&nbsp;Guangqing Zhou ,&nbsp;Jin'en Wu ,&nbsp;Huichen Guo ,&nbsp;Huiyun Chang ,&nbsp;Wei Liu","doi":"10.1016/j.antiviral.2024.106011","DOIUrl":"10.1016/j.antiviral.2024.106011","url":null,"abstract":"<div><div>Foot-and-mouth disease (FMD) is a highly contagious and economically devastating viral disease of ruminants and swine, badly affecting the livestock industry worldwide. In clinical practice, vaccination is a frequently employed strategy to prevent foot-and-mouth disease (FMDV). However, commercial inactivated vaccines for FMD mainly rely on humoral immunity, exhibiting poor cellular immune responses and causing adverse reactions. Here, we use the double emulsion method to prepare poly (lactic-co-glycolic acid) nanoparticles (PLGA-NP) encapsulated with IL-2 cytokines, wrap the dendritic cell (DC) membrane carrying FMDV antigen information on the surface of the nanoparticles, obtaining a biomimetic nanoparticle vaccine Biom@DC with uniform size. This vaccine can effortlessly move through lymph nodes due to its nanoscale size advantage. It also possesses DC ability to present antigens, and antigen presentation can be made more effective with high biocompatibility. The sustained release of IL-2 encapsulated in the core of PLGA-NP <em>in vivo</em> can effectively promote the body's cellular immune response. Immune tests on mice have shown that Biom@DC may greatly increase T cell activation and proliferation both <em>in vivo</em> and <em>in vitro</em>, while also significantly reducing the fraction of inhibitory Treg cells. Furthermore, in the micro serum neutralization assay for FMDV, it has been demonstrated that the group vaccinated with Biom@DC exhibits a clear neutralizing effect. Given its strong immunogenicity, Biom@DC has the potential to develop into a novel, potent anti-FMDV vaccination.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"231 ","pages":"Article 106011"},"PeriodicalIF":4.5,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142324106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical and clinical antiviral characterization of AB-836, a potent capsid assembly modulator against hepatitis B virus","authors":"Angela M. Lam ,&nbsp;Nagraj Mani ,&nbsp;Andrzej Ardzinski ,&nbsp;Kim Stever ,&nbsp;Andrea Cuconati ,&nbsp;Holly Micolochick Steuer ,&nbsp;Emily P. Thi ,&nbsp;Ingrid E. Graves ,&nbsp;Christine L. Espiritu ,&nbsp;Eugen Mesaros ,&nbsp;Steven G. Kultgen ,&nbsp;Kristi Fan ,&nbsp;Andrew G. Cole ,&nbsp;Troy O. Harasym ,&nbsp;Rene Rijnbrand ,&nbsp;Joanne Brown ,&nbsp;Timothy Eley ,&nbsp;Tilly Varughese ,&nbsp;Edward Gane ,&nbsp;Gaston Picchio ,&nbsp;Michael J. Sofia","doi":"10.1016/j.antiviral.2024.106010","DOIUrl":"10.1016/j.antiviral.2024.106010","url":null,"abstract":"<div><div>HBV capsid assembly modulators (CAMs) target the core protein and inhibit pregenomic RNA encapsidation and viral replication. HBV CAMs also interfere with cccDNA formation during <em>de novo</em> infection, which in turn suppresses transcription and production of HBV antigens. In this report, we describe the antiviral activities of AB-836, a potent and highly selective HBV CAM. AB-836 inhibited viral replication (EC₅₀ = 0.010 μM) in HepDE19 cells, and cccDNA formation (EC₅₀ = 0.18 μM) and HBsAg production (EC₅₀ = 0.20 μM) in HepG2-NTCP cells during <em>de novo</em> infection. AB-836 showed broad genotype coverage, remained active against variants resistant to nucleos(t)ide analogs, and demonstrated improved antiviral potency against core variants resistant to other CAMs. AB-836 also mediated potent inhibition of HBV replication in a hydrodynamic injection mouse model, reducing both serum and liver HBV DNA. In a Phase 1 clinical study, 28 days of once-daily AB-836 oral dosing at 50, 100, and 200 mg resulted in mean serum HBV DNA declines of 2.57, 3.04, and 3.55 log₁₀ IU/mL from baseline, respectively. Neither on-treatment viral rebound nor the emergence of viral resistance was observed during the 28-day treatment period. Furthermore, HBV DNA sequence analysis of baseline samples from the Phase 1 study revealed that 51.4% of the chronic hepatitis B participants contained at least one core polymorphism within the CAM-binding pocket, suggesting that genetic variations exist at this site. While AB-836 was discontinued due to clinical safety findings, data from the preclinical and clinical studies could help inform future optimization of HBV CAMs.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"231 ","pages":"Article 106010"},"PeriodicalIF":4.5,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142340063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural and quantitative comparison of viral infection-associated N-glycans in plasma from humans, pigs, and chickens: Greater similarity between humans and chickens than pigs","authors":"Mirae Kim ,&nbsp;Chi Soo Park ,&nbsp;Chulmin Moon,&nbsp;Jieun Kim,&nbsp;Subin Yang,&nbsp;Leeseul Jang,&nbsp;Ji Yeon Jang,&nbsp;Chang Myeong Jeong,&nbsp;Han Seul Lee,&nbsp;Kyuran Kim,&nbsp;Haeun Byeon,&nbsp;Ha Hyung Kim","doi":"10.1016/j.antiviral.2024.106009","DOIUrl":"10.1016/j.antiviral.2024.106009","url":null,"abstract":"<div><div>Host <em>N</em>-glycans play an essential role in the attachment, invasion, and infection processes of viruses, including zoonotic infectious diseases. The similarity of <em>N</em>-glycans in the trachea and lungs of humans and pigs facilitates the cross-species transmission of influenza viruses through respiratory tracts. In this study, the structure and quantity of <em>N</em>-glycans in the plasma of humans, pigs, and chickens were analyzed using liquid chromatography-quadrupole-Orbitrap-tandem mass spectrometry. <em>N</em>-glycans in humans (35), pigs (28), and chickens (53) were identified, including the most abundant, species-common, and species-specific <em>N</em>-glycans. Among the <em>N</em>-glycans (relative quantity &gt;0.5%), the sialic acid derivative of <em>N</em>-acetylneuraminic acid was identified in humans (the sum of the relative quantities of each; 64.3%), pigs (45.5%), and chickens (64.4%), whereas <em>N</em>-glycolylneuraminic acid was only identified in pigs (18.1%). Sialylated <em>N</em>-glycan linkage isomers are the influenza virus receptors (α2-6 in humans, α2-3 and α2-6 in pigs, and α2-3 in chickens). Only α2-6 linkages (human, 58.2%; pig, 44.8%; and chicken, 60.6%) were more abundant than α2-3/α2-6 linkages (human, 4.6%; pig, 0.6%; and chicken, 3.4%) and only α2-3 linkages (human, 1.5%; pig, 0.1%; and chicken, 0.4%). Fucosylation, which can promote viral infection through immune modulation, was more abundant in pigs (76.1%) than in humans (36.4%) and chickens (16.7%). Bisecting <em>N</em>-acetylglucosamine, which can suppress viral infection by inhibiting sialylation, was identified in humans (10.3%) and chickens (16.9%), but not in pigs. These results indicate that plasma <em>N</em>-glycans are similar in humans and chickens. This is the first study to compare plasma <em>N</em>-glycans in humans, pigs, and chickens.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"231 ","pages":"Article 106009"},"PeriodicalIF":4.5,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142340064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimization of Bangladesh and Malaysian genotype recombinant reporter Nipah viruses for in vitro antiviral screening and in vivo disease modeling","authors":"Michael K. Lo ,&nbsp;Shilpi Jain ,&nbsp;Katherine A. Davies ,&nbsp;Teresa E. Sorvillo ,&nbsp;Stephen R. Welch ,&nbsp;JoAnn D. Coleman-McCray ,&nbsp;Payel Chatterjee ,&nbsp;Anne L. Hotard ,&nbsp;Troy O'Neal ,&nbsp;Mike Flint ,&nbsp;Huiwang Ai ,&nbsp;Cesar G. Albariño ,&nbsp;Jessica R. Spengler ,&nbsp;Joel M. Montgomery ,&nbsp;Christina F. Spiropoulou","doi":"10.1016/j.antiviral.2024.106013","DOIUrl":"10.1016/j.antiviral.2024.106013","url":null,"abstract":"<div><div>Nipah virus (NiV) causes near-annual outbreaks of fatal encephalitis and respiratory disease in South Asia with a high mortality rate (∼70%). Since there are no approved therapeutics for NiV disease in humans, the WHO has designated NiV and henipaviral diseases priority pathogens for research and development. We generated a new recombinant green fluorescent reporter NiV of the circulating Bangladesh genotype (rNiV-B-ZsG) and optimized it alongside our previously generated Malaysian genotype reporter counterpart (rNiV-M-ZsG) for antiviral screening in primary-like human respiratory cell types. Validating our platform for rNiV-B-ZsG with a synthetic compound library directed against viral RNA-dependent RNA polymerases, we identified a hit compound and confirmed its sub-micromolar activity against wild-type NiV, green fluorescent reporter, and the newly constructed bioluminescent red fluorescent double reporter (rNiV-B-BREP) NiV. We furthermore demonstrated that rNiV-B-ZsG and rNiV-B-BREP viruses showed pathogenicity comparable to wild-type NiV-B in the Syrian golden hamster model of disease, supporting additional use of these tools for both pathogenesis and advanced pre-clinical studies <em>in vivo</em>.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"231 ","pages":"Article 106013"},"PeriodicalIF":4.5,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142340062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Orally bioavailable RORγ/DHODH dual host-targeting small molecules with broad-spectrum antiviral activity","authors":"Alexandra Herrmann ,&nbsp;Christian Gege ,&nbsp;Christina Wangen ,&nbsp;Sabrina Wagner ,&nbsp;Melanie Kögler ,&nbsp;Arne Cordsmeier ,&nbsp;Pascal Irrgang ,&nbsp;Wing-Hang Ip ,&nbsp;Tatjana Weil ,&nbsp;Victoria Hunszinger ,&nbsp;Rüdiger Groß ,&nbsp;Natalie Heinen ,&nbsp;Stephanie Pfaender ,&nbsp;Sebastian Reuter ,&nbsp;Robert Klopfleisch ,&nbsp;Nadja Uhlig ,&nbsp;Valentina Eberlein ,&nbsp;Leila Issmail ,&nbsp;Thomas Grunwald ,&nbsp;Benjamin Hietel ,&nbsp;Friedrich Hahn","doi":"10.1016/j.antiviral.2024.106008","DOIUrl":"10.1016/j.antiviral.2024.106008","url":null,"abstract":"<div><div>Host-directed antivirals (HDAs) represent an attractive treatment option and a strategy for pandemic preparedness, especially due to their potential broad-spectrum antiviral activity and high barrier to resistance development. Particularly, dual-targeting HDAs offer a promising approach for antiviral therapy by simultaneously disrupting multiple pathways essential for viral replication.</div><div>Izumerogant (IMU-935) targets two host proteins, (i) the retinoic acid receptor-related orphan receptor γ isoform 1 (RORγ1), which modulates cellular cholesterol metabolism, and (ii) the enzyme dihydroorotate dehydrogenase (DHODH), which is involved in <em>de novo</em> pyrimidine synthesis. Here, we synthesized optimized derivatives of izumerogant and characterized their antiviral activity in comparison to a recently described structurally distinct RORγ/DHODH dual inhibitor. Cell culture-based infection models for enveloped and non-enveloped DNA and RNA viruses, as well as a retrovirus, demonstrated high potency and broad-spectrum activity against human viral pathogens for RORγ/DHODH dual inhibitors at nanomolar concentrations. Comparative analyses with equipotent single-target inhibitors in metabolite supplementation approaches revealed that the dual-targeting mode represents the mechanistic basis for the potent antiviral activity. For SARS-CoV-2, an optimized dual inhibitor completely blocked viral replication in human airway epithelial cells at 5 nM and displayed a synergistic drug interaction with the nucleoside analog molnupiravir. In a SARS-CoV-2 mouse model, treatment with a dual inhibitor alone, or in combination with molnupiravir, reduced the viral load by 7- and 58-fold, respectively.</div><div>Considering the clinical safety, oral bioavailability, and tolerability of izumerogant in a recent Phase I study, izumerogant-like drugs represent potent dual-targeting antiviral HDAs with pronounced broad-spectrum activity for further clinical development.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"231 ","pages":"Article 106008"},"PeriodicalIF":4.5,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142279790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulating apoptosis as a novel therapeutic strategy against Respiratory Syncytial Virus infection: insights from Rotenone","authors":"Ke Zhang ,&nbsp;Xiao-Meng Yang ,&nbsp;Haoran Sun ,&nbsp;Zhong-Shan Cheng ,&nbsp;Jianqing Peng ,&nbsp;Minjun Dong ,&nbsp;Fang Chen ,&nbsp;Huyan Shen ,&nbsp;Pingping Zhang ,&nbsp;Jin-Fu Li ,&nbsp;Yong Zhang ,&nbsp;Chunlai Jiang ,&nbsp;Jiandong Huang ,&nbsp;Jasper Fuk-Woo Chan ,&nbsp;Shuofeng Yuan ,&nbsp;Yu-Si Luo ,&nbsp;Xiang-Chun Shen","doi":"10.1016/j.antiviral.2024.106007","DOIUrl":"10.1016/j.antiviral.2024.106007","url":null,"abstract":"<div><div>Respiratory syncytial virus (RSV) is a significant cause of acute lower respiratory tract infections, particularly in vulnerable populations such as neonates, infants, young children, and the elderly. Among infants, RSV is the primary cause of bronchiolitis and pneumonia, contributing to a notable proportion of child mortality under the age of 5. In this study, we focused on investigating the pathogenicity of a lethal RSV strain, GZ08-18, as a model for understanding mechanisms of hypervirulent RSV. Our findings indicate that the heightened pathogenicity of GZ08-18 stems from compromised activation of intrinsic apoptosis, as evidenced by aberration of mitochondrial membrane depolarization in host cells. We thus hypothesized that enhancing intrinsic apoptosis could potentially attenuate the virulence of RSV strains and explored the effects of Rotenone, a natural compound known to stimulate the intrinsic apoptosis pathway, on inhibiting RSV infection. Our results demonstrate that Rotenone treatment significantly improved mouse survival rates and mitigated lung pathology following GZ08-18 infection. These findings suggest that modulating the suppressed apoptosis induced by RSV infection represents a promising avenue for antiviral intervention strategies.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"231 ","pages":"Article 106007"},"PeriodicalIF":4.5,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142279789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of antibody-resistant SARS-CoV-2 mutants via N4-Hydroxycytidine mutagenesis","authors":"Priya Kumar ,&nbsp;Xiaoxiao Zhang ,&nbsp;Rahul Shaha ,&nbsp;Maik Kschischo ,&nbsp;Matthias Dobbelstein","doi":"10.1016/j.antiviral.2024.106006","DOIUrl":"10.1016/j.antiviral.2024.106006","url":null,"abstract":"<div><p>Monoclonal antibodies targeting the Spike protein of SARS-CoV-2 are effective against COVID-19 and might mitigate future pandemics. However, their efficacy is challenged by the emergence of antibody-resistant virus variants. We developed a method to efficiently identify such resistant mutants based on selection from mutagenized virus pools. By inducing mutations with the active compound of Molnupiravir, N4-hydroxycytidine (NHC), and subsequently passaging the virus in the presence of antibodies, we identified specific Spike mutations linked to resistance. Validation of these mutations was conducted using pseudotypes and immunofluorescence analysis. From a Wuhan-like strain of SARS-CoV-2, we identified the following mutations conferring strong resistance towards the corresponding antibodies: Bamlanivimab – E484K, F490S and S494P; Sotrovimab – E340K; Cilgavimab – K444R/E and N450D. From the Omicron B.1.1.529 variant, the strongly selected mutations were: Bebtelovimab – V445A; Sotrovimab – E340K and K356M; Cilgavimab – K444R, V445A and N450D. We also identified escape mutations in the Wuhan-like Spike for the broadly neutralizing antibodies S2K146 – combined G485S and Q493R – and S2H97 – D428G, K462E and S514F. Structural analysis revealed that the selected mutations occurred at antibody-binding residues within the receptor-binding domains of the Spike protein. Most of the selected mutants largely maintained ACE2 binding and infectivity. Notably, many of the identified resistance-conferring mutations are prevalent in real-world SARS-CoV-2 variants, but some of them (G485S, D428G, and K462E) have not yet been observed in circulating strains. Our approach offers a strategy for predicting the therapeutic efficacy of antibodies against emerging virus variants.</p></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"231 ","pages":"Article 106006"},"PeriodicalIF":4.5,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0166354224002158/pdfft?md5=9ab9e705cbef7503c5495cd2cc8afff3&pid=1-s2.0-S0166354224002158-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142274202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The ApoA1-mimetic peptide 4F blocks flavivirus NS1-triggered endothelial dysfunction and protects against lethal dengue virus challenge","authors":"Pedro H. Carneiro ,&nbsp;E. Vanessa Jimenez-Posada ,&nbsp;Eduarda Lopes ,&nbsp;Ronaldo Mohana-Borges ,&nbsp;Scott B. Biering ,&nbsp;Eva Harris","doi":"10.1016/j.antiviral.2024.106002","DOIUrl":"10.1016/j.antiviral.2024.106002","url":null,"abstract":"<div><p>Flavivirus infections result in a variety of outcomes, from clinically inapparent infections to severe, sometimes fatal cases characterized by hemorrhagic manifestations and vascular leakage leading to shock (dengue), meningomyeloencephalitis (West Nile), and congenital abnormalities (Zika). Although there are approved vaccines against several flaviviruses, potentially enhancing cross-reactive immune responses have complicated the development and implementation of vaccines against dengue and Zika viruses, and no specific therapeutics currently exist. The flavivirus nonstructural protein 1 (NS1) is a promising antiviral target because it is a conserved multifunctional virulence factor that directly triggers vascular leak. We previously showed that interactions between NS1 and the ApoA1 lipoprotein modulate DENV infection. Here, we evaluated the potential of the ApoA1-mimetic peptide, 4F, to interfere with endothelial dysfunction mediated by the NS1 protein of dengue, Zika, and West Nile flaviviruses. In an <em>in vitro</em> model consisting of human endothelial cell monolayers, 4F inhibited NS1-induced hyperpermeability, as measured by a transendothelial electrical resistance assay, and prevented NS1-triggered disruption of the endothelial glycocalyx layer. We also demonstrate that treatment with 4F inhibited NS1 interaction with endothelial cells. Finally, we show that 4F protects against lethal DENV challenge in a mouse model, reducing morbidity and mortality in a dose-dependent manner. Our data demonstrate the potential of 4F to inhibit flavivirus NS1-mediated pathology and severe dengue disease in mice and suggest that 4F can also serve as a molecular tool to probe different NS1 functions <em>in vitro</em> and <em>in vivo</em>.</p></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"231 ","pages":"Article 106002"},"PeriodicalIF":4.5,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142242495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}