Analgesics
Antiandrogens
Antihistamines
Azvudine
Bromhexine
Budesonide
Colchicine
Conv. Plasma
Curcumin
Famotidine
Favipiravir
Fluvoxamine
Hydroxychlor..
Ivermectin
Lifestyle
Melatonin
Metformin
Minerals
Molnupiravir
Monoclonals
Naso/orophar..
Nigella Sativa
Nitazoxanide
PPIs
Paxlovid
Quercetin
Remdesivir
Thermotherapy
Vitamins
More

Other
Feedback
Home
Top
Abstract
All miscellaneous studies
Meta analysis
 
Feedback
Home
next
study
previous
study
c19early.org COVID-19 treatment researchSelect treatment..Select..
Melatonin Meta
Metformin Meta
Antihistamines Meta
Azvudine Meta Molnupiravir Meta
Bromhexine Meta
Budesonide Meta
Colchicine Meta Nigella Sativa Meta
Conv. Plasma Meta Nitazoxanide Meta
Curcumin Meta PPIs Meta
Famotidine Meta Paxlovid Meta
Favipiravir Meta Quercetin Meta
Fluvoxamine Meta Remdesivir Meta
Hydroxychlor.. Meta Thermotherapy Meta
Ivermectin Meta

Recent:   

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

Fiaschi et al., Viruses, doi:10.3390/v16020168
Jan 2024  
  Post
  Facebook
Share
  Source   PDF  
In vitro study showing additive or synergistic antiviral effects with combinations of COVID-19 therapeutics nirmatrelvir, molnupiravir, remdesivir, and monoclonal antibodies sotrovimab, bebtelovimab, cilgavimab and tixagevimab against ancestral B.1 and Omicron BQ.1.1 SARS-CoV-2 variants in Vero E6 cells. Authors found specific concentrations of antiviral pairs with higher than expected cooperative effects, including marked synergistic shifts in IC50 values, although overall weighted synergy scores indicated additivity. Combinations were similarly effective against both viruses. Confirmation experiments supported synergistic interactions, especially for dual antiviral combinations, while cooperative effects between remdesivir and monoclonal antibodies were less pronounced.
Fiaschi et al., 23 Jan 2024, peer-reviewed, 9 authors. Contact: vicenti@unisi.it (corresponding author), lia.fiaschi@unisi.it, camilla.biba@student.unisi.it, ilenia.varasi@student.unisi.it, niccolo.bartolini@student.unisi.it, c.paletti@student.unisi.it, federica.giammari@gmail.com, saladini6@unisi.it, maurizio.zazzi@unisi.it.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperMiscellaneousAll
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
Lia Fiaschi, Camilla Biba, Ilenia Varasi, Niccolò Bartolini, Chiara Paletti, Federica Giammarino, Francesco Saladini, Maurizio Zazzi, Ilaria Vicenti
Viruses, doi:10.3390/v16020168
Combination antiviral therapy may be helpful in the treatment of SARS-CoV-2 infection; however, no clinical trial data are available, and combined use of direct-acting antivirals (DAA) and monoclonal antibodies (mAb) has been reported only anecdotally. To assess the cooperative effects of dual drug combinations in vitro, we used a VERO E6 cell-based in vitro system with the ancestral B.1 or the highly divergent BQ.1.1 virus to test pairwise combinations of the licensed DAA, including nirmatrelvir (NRM), remdesivir (RDV) and the active metabolite of molnupiravir (EIDD-1931) as well the combination of RDV with four licensed mAbs (sotrovimab, bebtelovimab, cilgavimab, tixagevimab; tested only with the susceptible B.1 virus). According to SynergyFinder 3.0 summary and weighted scores, all the combinations had an additive effect. Within DAA/DAA combinations, paired scores with the B.1 and BQ.1.1 variants were comparable. In the post hoc analysis weighting synergy by concentrations, several cases of highly synergistic scores were detected at specific drug concentrations, both for DAA/DAA and for RDV/mAb combinations. This was supported by in vitro confirmation experiments showing a more than a linear shift of a drug-effective concentration (IC 50 ) at increasing concentrations of the companion drug, although the effect was prominent with DAA/DAA combinations and minimal or null with RDV/mAb combinations. These results support the cooperative effects of dual drug combinations in vitro, which should be further investigated in animal models before introduction into the clinic.
importantly, in vivo experiments should be designed in a suitable animal model before moving forward to a wide introduction of combination therapy into the clinic. SARS-CoV-2 animal models have been progressively improved [37] and should now be an integral part of the lessons learned from the COVID-19 pandemic [9] . Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/v16020168/s1, Table S1 : IC 50 synergistic potency shift measured in infected VERO E6 cells; Figure S1 : Bi-dimensional (2D) synergy plots of antivirals against the two SARS-CoV-2 strains tested, generated using Synergy Finder 3.0 (https://synergyfinder.fimm.fi/ accessed on 12 October 2023); Figure S2 : Overall combinatorial effects of the three DAA pairs as well as those of the three RDV/mAb groups compared by the Kruskal-Wallis test followed by Mann-Whitney pairwise comparisons between groups. Author Contributions Conflicts of Interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
References
Abdelnabi, Maes, De Jonghe, Weynand, Neyts, Combination of the Parent Analogue of Remdesivir (GS-441524) and Molnupiravir Results in a Markedly Potent Antiviral Effect in SARS-CoV-2 Infected Syrian Hamsters, Front. Pharmacol, doi:10.3389/fphar.2022.1072202
Ahmadi, Zadheidar, Sadeghi, Nejati, Salimi et al., SARS-CoV-2 Intrahost Evolution in Immunocompromised Patients in Comparison with Immunocompetent Populations after Treatment, J. Med. Virol, doi:10.1002/jmv.28877
Cho, Shin, Yang, Kim, Kim et al., Evaluation of Antiviral Drugs against Newly Emerged SARS-CoV-2 Omicron Subvariants, Antivir. Res, doi:10.1016/j.antiviral.2023.105609
Del Borgo, Garattini, Bortignon, Carraro, Di Trento et al., Tolerability and Prescribing Choice of Antiviral Molecules Molnupiravir, Remdesivir and Nirmatrelvir/r: A Real-World Comparison in the First Ten Months of Use, Viruses, doi:10.3390/v15041025
Fiaschi, Dragoni, Schiaroli, Bergna, Rossetti et al., Efficacy of Licensed Monoclonal Antibodies and Antiviral Agents against the SARS-CoV-2 Omicron Sublineages BA.1 and BA.2, Viruses, doi:10.3390/v14071374
Foucquier, Guedj, Analysis of Drug Combinations: Current Methodological Landscape, Pharmacol. Res. Perspect, doi:10.1002/prp2.149
Fuentealba-Manosalva, Mansilla, Buelvas, Martin-Martin, Torres et al., Mind the Curve: Dose-Response Fitting Biases the Synergy Scores across Software Used for Chemotherapy Combination Studies, Int. J. Mol. Sci, doi:10.3390/ijms24119705
Gidari, Sabbatini, Schiaroli, Bastianelli, Pierucci et al., Synergistic Activity of Remdesivir-Nirmatrelvir Combination on a SARS-CoV-2 In Vitro Model and a Case Report, Viruses, doi:10.3390/v15071577
Gidari, Sabbatini, Schiaroli, Bastianelli, Pierucci et al., The Combination of Molnupiravir with Nirmatrelvir or GC376 Has a Synergic Role in the Inhibition of SARS-CoV-2 Replication In Vitro, Microorganisms, doi:10.3390/microorganisms10071475
Hogan, Duerr, Dimartino, Marier, Hochman et al., Remdesivir Resistance in Transplant Recipients with Persistent Coronavirus Disease, Clin. Infect. Dis, doi:10.1093/cid/ciac769
Ianevski, Giri, Aittokallio, SynergyFinder 3.0: An Interactive Analysis and Consensus Interpretation of Multi-Drug Synergies across Multiple Samples, Nucleic Acids Res, doi:10.1093/nar/gkac382
Jeong, Chokkakula, Min, Kim, Choi et al., Combination Therapy with Nirmatrelvir and Molnupiravir Improves the Survival of SARS-CoV-2 Infected Mice, Antivir. Res, doi:10.1016/j.antiviral.2022.105430
Koszalka, Subbarao, Baz, Preclinical and Clinical Developments for Combination Treatment of Influenza, PLoS Pathog, doi:10.1371/journal.ppat.1010481
Lanzafame, Gottardi, Guella, Collini, Costa et al., Successful Treatment of Persistent SARS-CoV-2 Infection with Nirmatrelvir/Ritonavir plus Sotrovimab in Four Immunocompromised Patients, J. Chemother, doi:10.1080/1120009X.2023.2196917
Li, Hilgenfeld, Whitley, De Clercq, Therapeutic Strategies for COVID-19: Progress and Lessons Learned, Nat. Rev. Drug Discov, doi:10.1038/s41573-023-00672-y
Lin, Lu, Hong, Li, Chen et al., Animal models for studying coronavirus infections and developing antiviral agents and vaccines, Antivir. Res, doi:10.1016/j.antiviral.2022.105345
Marangoni, Antonello, Coppi, Palazzo, Nassi et al., Combination Regimen of Nirmatrelvir/Ritonavir and Molnupiravir for the Treatment of Persistent SARS-CoV-2 Infection: A Case Report and a Scoping Review of the Literature, Int. J. Infect. Dis, doi:10.1016/j.ijid.2023.04.412
Menegale, Manica, Zardini, Guzzetta, Marziano et al., Evaluation of Waning of SARS-CoV-2 Vaccine-Induced Immunity: A Systematic Review and Meta-Analysis, JAMA Netw. Open, doi:10.1001/jamanetworkopen.2023.10650
Mikulska, Sepulcri, Dentone, Magne, Balletto et al., Triple Combination Therapy with 2 Antivirals and Monoclonal Antibodies for Persistent or Relapsed Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Immunocompromised Patients, Clin. Infect. Dis, doi:10.1093/cid/ciad181
Mustafa, Stern, Patel, Chu, COVID-19 Treatments: Then and Now, J. Allergy Clin. Immunol. Pract, doi:10.1016/j.jaip.2023.07.045
Nguyenla, Wehri, Van Dis, Biering, Yamashiro et al., Discovery of SARS-CoV-2 Antiviral Synergy between Remdesivir and Approved Drugs in Human Lung Cells, Sci. Rep, doi:10.1038/s41598-022-21034-5
Plebani, Bai, Si, Li, Zhang et al., 3D Lung Tissue Models for Studies on SARS-CoV-2 Pathophysiology and Therapeutics, Int. J. Mol. Sci, doi:10.3390/ijms231710071
Qu, Faraone, Evans, Zheng, Carlin et al., Enhanced Evasion of Neutralizing Antibody Response by Omicron XBB.1.5, CH.1.1, and CA.3.1 Variants, Cell Rep, doi:10.1016/j.celrep.2023.112443
Semenzato, Botton, Drouin, Baricault, Bertrand et al., Characteristics Associated with the Residual Risk of Severe COVID-19 after a Complete Vaccination Schedule: A Cohort Study of 28 Million People in France, Lancet Reg. Health. Eur, doi:10.1016/j.lanepe.2022.100441
Shyr, Cheng, Lo, Zheng, Drug Combination Therapy for Emerging Viral Diseases, Drug Discov. Today, doi:10.1016/j.drudis.2021.05.008
Touret, Giraud, Bourret, Donati, Tran-Rajau et al., Enhanced Neutralization Escape to Therapeutic Monoclonal Antibodies by SARS-CoV-2 Omicron Sub-Lineages, iScience, doi:10.1016/j.isci.2023.106413
Turtle, Thorpe, Drake, Swets, Palmieri et al., Outcome of COVID-19 in Hospitalised Immunocompromised Patients: An Analysis of the WHO ISARIC CCP-UK Prospective Cohort Study, PLoS Med, doi:10.1371/journal.pmed.1004086
Vicenti, Martina, Boccuto, De Angelis, Giavarini et al., System-Oriented Optimization of Multi-Target 2,6-Diaminopurine Derivatives: Easily Accessible Broad-Spectrum Antivirals Active against Flaviviruses, Influenza Virus and SARS-CoV-2, Eur. J. Med. Chem, doi:10.1016/j.ejmech.2021.113683
Wagoner, Herring, Hsiang, Ianevski, Biering et al., Combinations of Host-and Virus-Targeting Antiviral Drugs Confer Synergistic Suppression of SARS-CoV-2, Microbiol. Spectr, doi:10.1128/spectrum.03331-22
Wang, Sacramento, Jockusch, Chaves, Tao et al., Combination of Antiviral Drugs Inhibits SARS-CoV-2 Polymerase and Exonuclease and Demonstrates COVID-19 Therapeutic Potential in Viral Cell Culture, Commun. Biol, doi:10.1038/s42003-022-03101-9
Wooten, Meyer, Lubbock, Quaranta, Lopez, MuSyC Is a Consensus Framework That Unifies Multi-Drug Synergy Metrics for Combinatorial Drug Discovery, Nat. Commun, doi:10.1038/s41467-021-24789-z
Wu, Carr, Harvey, Mears, Kjaer et al., WHO's Therapeutics and COVID-19 Living Guideline on MAbs Needs to Be Reassessed, Lancet, doi:10.1016/S0140-6736(22)01938-9
Yadav, Wennerberg, Aittokallio, Tang, Searching for Drug Synergy in Complex Dose-Response Landscapes Using an Interaction Potency Model, Comput. Struct. Biotechnol. J, doi:10.1016/j.csbj.2015.09.001
Yan, Yan, Viral Target and Metabolism-Based Rationale for Combined Use of Recently Authorized Small Molecule COVID-19 Medicines: Molnupiravir, Nirmatrelvir, and Remdesivir, Fundam. Clin. Pharmacol, doi:10.1111/fcp.12889
Yang, Multani, Garrigues, Oh, Hemarajata et al., Transient SARS-CoV-2 RNA-Dependent RNA Polymerase Mutations after Remdesivir Treatment for Chronic COVID-19 in Two Transplant Recipients: Case Report and Intra-Host Viral Genomic Investigation, Microorganisms, doi:10.3390/microorganisms11082096
Zhu, Binder, Yurgelonis, Rai, Lazarro et al., Generation of a VeroE6 Pgp Gene Knock out Cell Line and Its Use in SARS-CoV-2 Antiviral Study, Antivir. Res, doi:10.1016/j.antiviral.2022.105429
Zuckerman, Bucris, Keidar-Friedman, Amsalem, Brosh-Nissimov, Nirmatrelvir Resistance-de Novo E166V/L50V Mutations in an Immunocompromised Patient Treated with Prolonged Nirmatrelvir/Ritonavir Monotherapy Leading to Clinical and Virological Treatment Failure-A Case Report, Clin. Infect. Dis, doi:10.1093/cid/ciad494
{ 'indexed': {'date-parts': [[2024, 1, 24]], 'date-time': '2024-01-24T00:33:48Z', 'timestamp': 1706056428724}, 'reference-count': 37, 'publisher': 'MDPI AG', 'issue': '2', 'license': [ { 'start': { 'date-parts': [[2024, 1, 23]], 'date-time': '2024-01-23T00:00:00Z', 'timestamp': 1705968000000}, 'content-version': 'vor', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0/'}], 'funder': [ {'name': 'Ministero dell’Università e della Ricerca', 'award': ['202022GZEHE_01']}, { 'name': 'EU funding within the NextGenerationEU-MUR PNRR Extended Partnership initiative on ' 'Emerging Infectious Diseases', 'award': ['PE00000007']}, { 'DOI': '10.13039/501100000780', 'name': 'European Union’s Horizon Europe Research and Innovation Program', 'doi-asserted-by': 'publisher', 'award': ['101046016']}], 'content-domain': {'domain': [], 'crossmark-restriction': False}, 'abstract': '<jats:p>Combination antiviral therapy may be helpful in the treatment of SARS-CoV-2 ' 'infection; however, no clinical trial data are available, and combined use of direct-acting ' 'antivirals (DAA) and monoclonal antibodies (mAb) has been reported only anecdotally. To ' 'assess the cooperative effects of dual drug combinations in vitro, we used a VERO E6 ' 'cell-based in vitro system with the ancestral B.1 or the highly divergent BQ.1.1 virus to ' 'test pairwise combinations of the licensed DAA, including nirmatrelvir (NRM), remdesivir ' '(RDV) and the active metabolite of molnupiravir (EIDD-1931) as well the combination of RDV ' 'with four licensed mAbs (sotrovimab, bebtelovimab, cilgavimab, tixagevimab; tested only with ' 'the susceptible B.1 virus). According to SynergyFinder 3.0 summary and weighted scores, all ' 'the combinations had an additive effect. Within DAA/DAA combinations, paired scores with the ' 'B.1 and BQ.1.1 variants were comparable. In the post hoc analysis weighting synergy by ' 'concentrations, several cases of highly synergistic scores were detected at specific drug ' 'concentrations, both for DAA/DAA and for RDV/mAb combinations. This was supported by in vitro ' 'confirmation experiments showing a more than a linear shift of a drug-effective concentration ' '(IC50) at increasing concentrations of the companion drug, although the effect was prominent ' 'with DAA/DAA combinations and minimal or null with RDV/mAb combinations. These results ' 'support the cooperative effects of dual drug combinations in vitro, which should be further ' 'investigated in animal models before introduction into the clinic.</jats:p>', 'DOI': '10.3390/v16020168', 'type': 'journal-article', 'created': {'date-parts': [[2024, 1, 23]], 'date-time': '2024-01-23T12:22:32Z', 'timestamp': 1706012552000}, 'page': '168', 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': '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', 'prefix': '10.3390', 'volume': '16', 'author': [ { 'ORCID': 'http://orcid.org/0000-0003-3599-7384', 'authenticated-orcid': False, 'given': 'Lia', 'family': 'Fiaschi', 'sequence': 'first', 'affiliation': [ { 'name': 'Department of Medical Biotechnologies, University of Siena, ' '53100 Siena, Italy'}]}, { 'given': 'Camilla', 'family': 'Biba', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Medical Biotechnologies, University of Siena, ' '53100 Siena, Italy'}]}, { 'given': 'Ilenia', 'family': 'Varasi', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Medical Biotechnologies, University of Siena, ' '53100 Siena, Italy'}]}, { 'ORCID': 'http://orcid.org/0000-0002-2314-1434', 'authenticated-orcid': False, 'given': 'Niccolò', 'family': 'Bartolini', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Medical Biotechnologies, University of Siena, ' '53100 Siena, Italy'}]}, { 'ORCID': 'http://orcid.org/0009-0004-1018-9545', 'authenticated-orcid': False, 'given': 'Chiara', 'family': 'Paletti', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Medical Biotechnologies, University of Siena, ' '53100 Siena, Italy'}]}, { 'given': 'Federica', 'family': 'Giammarino', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Medical Biotechnologies, University of Siena, ' '53100 Siena, Italy'}]}, { 'ORCID': 'http://orcid.org/0000-0002-9934-377X', 'authenticated-orcid': False, 'given': 'Francesco', 'family': 'Saladini', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Medical Biotechnologies, University of Siena, ' '53100 Siena, Italy'}]}, { 'ORCID': 'http://orcid.org/0000-0002-0344-6281', 'authenticated-orcid': False, 'given': 'Maurizio', 'family': 'Zazzi', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Medical Biotechnologies, University of Siena, ' '53100 Siena, Italy'}]}, { 'ORCID': 'http://orcid.org/0000-0002-4306-2960', 'authenticated-orcid': False, 'given': 'Ilaria', 'family': 'Vicenti', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Medical Biotechnologies, University of Siena, ' '53100 Siena, Italy'}]}], 'member': '1968', 'published-online': {'date-parts': [[2024, 1, 23]]}, 'reference': [ { 'key': 'ref_1', 'doi-asserted-by': 'crossref', 'first-page': '100441', 'DOI': '10.1016/j.lanepe.2022.100441', 'article-title': 'Characteristics Associated with the Residual Risk of Severe COVID-19 ' 'after a Complete Vaccination Schedule: A Cohort Study of 28 Million ' 'People in France', 'volume': '19', 'author': 'Semenzato', 'year': '2022', 'journal-title': 'Lancet Reg. Health. Eur.'}, { 'key': 'ref_2', 'doi-asserted-by': 'crossref', 'unstructured': 'Turtle, L., Thorpe, M., Drake, T.M., Swets, M., Palmieri, C., Russell, ' 'C.D., Ho, A., Aston, S., Wootton, D.G., and Richter, A. (2023). Outcome ' 'of COVID-19 in Hospitalised Immunocompromised Patients: An Analysis of ' 'the WHO ISARIC CCP-UK Prospective Cohort Study. PLoS Med., 20.', 'DOI': '10.1371/journal.pmed.1004086'}, { 'key': 'ref_3', 'doi-asserted-by': 'crossref', 'first-page': '112443', 'DOI': '10.1016/j.celrep.2023.112443', 'article-title': 'Enhanced Evasion of Neutralizing Antibody Response by Omicron XBB.1.5, ' 'CH.1.1, and CA.3.1 Variants', 'volume': '42', 'author': 'Qu', 'year': '2023', 'journal-title': 'Cell Rep.'}, { 'key': 'ref_4', 'doi-asserted-by': 'crossref', 'first-page': 'e2310650', 'DOI': '10.1001/jamanetworkopen.2023.10650', 'article-title': 'Evaluation of Waning of SARS-CoV-2 Vaccine-Induced Immunity: A ' 'Systematic Review and Meta-Analysis', 'volume': '6', 'author': 'Menegale', 'year': '2023', 'journal-title': 'JAMA Netw. Open'}, { 'key': 'ref_5', 'doi-asserted-by': 'crossref', 'first-page': '3321', 'DOI': '10.1016/j.jaip.2023.07.045', 'article-title': 'COVID-19 Treatments: Then and Now', 'volume': '11', 'author': 'Mustafa', 'year': '2023', 'journal-title': 'J. Allergy Clin. Immunol. Pract.'}, { 'key': 'ref_6', 'doi-asserted-by': 'crossref', 'first-page': '106413', 'DOI': '10.1016/j.isci.2023.106413', 'article-title': 'Enhanced Neutralization Escape to Therapeutic Monoclonal Antibodies by ' 'SARS-CoV-2 Omicron Sub-Lineages', 'volume': '26', 'author': 'Touret', 'year': '2023', 'journal-title': 'iScience'}, { 'key': 'ref_7', 'doi-asserted-by': 'crossref', 'first-page': '105609', 'DOI': '10.1016/j.antiviral.2023.105609', 'article-title': 'Evaluation of Antiviral Drugs against Newly Emerged SARS-CoV-2 Omicron ' 'Subvariants', 'volume': '214', 'author': 'Cho', 'year': '2023', 'journal-title': 'Antivir. Res.'}, { 'key': 'ref_8', 'doi-asserted-by': 'crossref', 'unstructured': 'Del Borgo, C., Garattini, S., Bortignon, C., Carraro, A., Di Trento, D., ' 'Gasperin, A., Grimaldi, A., De Maria, S.G., Corazza, S., and Tieghi, T. ' '(2023). Effectiveness, Tolerability and Prescribing Choice of Antiviral ' 'Molecules Molnupiravir, Remdesivir and Nirmatrelvir/r: A Real-World ' 'Comparison in the First Ten Months of Use. Viruses, 15.', 'DOI': '10.3390/v15041025'}, { 'key': 'ref_9', 'doi-asserted-by': 'crossref', 'first-page': '449', 'DOI': '10.1038/s41573-023-00672-y', 'article-title': 'Therapeutic Strategies for COVID-19: Progress and Lessons Learned', 'volume': '22', 'author': 'Li', 'year': '2023', 'journal-title': 'Nat. Rev. Drug Discov.'}, { 'key': 'ref_10', 'doi-asserted-by': 'crossref', 'first-page': '2367', 'DOI': '10.1016/j.drudis.2021.05.008', 'article-title': 'Drug Combination Therapy for Emerging Viral Diseases', 'volume': '26', 'author': 'Shyr', 'year': '2021', 'journal-title': 'Drug Discov. Today'}, { 'key': 'ref_11', 'doi-asserted-by': 'crossref', 'unstructured': 'Gidari, A., Sabbatini, S., Schiaroli, E., Bastianelli, S., Pierucci, S., ' 'Busti, C., Comez, L., Libera, V., Macchiarulo, A., and Paciaroni, A. ' '(2022). The Combination of Molnupiravir with Nirmatrelvir or GC376 Has a ' 'Synergic Role in the Inhibition of SARS-CoV-2 Replication In Vitro. ' 'Microorganisms, 10.', 'DOI': '10.20944/preprints202206.0272.v1'}, { 'key': 'ref_12', 'doi-asserted-by': 'crossref', 'first-page': '18506', 'DOI': '10.1038/s41598-022-21034-5', 'article-title': 'Discovery of SARS-CoV-2 Antiviral Synergy between Remdesivir and ' 'Approved Drugs in Human Lung Cells', 'volume': '12', 'author': 'Nguyenla', 'year': '2022', 'journal-title': 'Sci. Rep.'}, { 'key': 'ref_13', 'doi-asserted-by': 'crossref', 'unstructured': 'Wagoner, J., Herring, S., Hsiang, T.-Y., Ianevski, A., Biering, S.B., ' 'Xu, S., Hoffmann, M., Pöhlmann, S., Gale, M., and Aittokallio, T. ' '(2022). Combinations of Host- and Virus-Targeting Antiviral Drugs Confer ' 'Synergistic Suppression of SARS-CoV-2. Microbiol. Spectr., 10.', 'DOI': '10.1128/spectrum.03331-22'}, { 'key': 'ref_14', 'doi-asserted-by': 'crossref', 'unstructured': 'Wang, X., Sacramento, C.Q., Jockusch, S., Chaves, O.A., Tao, C., ' 'Fintelman-Rodrigues, N., Chien, M., Temerozo, J.R., Li, X., and Kumar, ' 'S. (2022). Combination of Antiviral Drugs Inhibits SARS-CoV-2 Polymerase ' 'and Exonuclease and Demonstrates COVID-19 Therapeutic Potential in Viral ' 'Cell Culture. Commun. Biol., 5.', 'DOI': '10.1038/s42003-022-03101-9'}, { 'key': 'ref_15', 'doi-asserted-by': 'crossref', 'first-page': '1072202', 'DOI': '10.3389/fphar.2022.1072202', 'article-title': 'Combination of the Parent Analogue of Remdesivir (GS-441524) and ' 'Molnupiravir Results in a Markedly Potent Antiviral Effect in ' 'SARS-CoV-2 Infected Syrian Hamsters', 'volume': '13', 'author': 'Abdelnabi', 'year': '2022', 'journal-title': 'Front. Pharmacol.'}, { 'key': 'ref_16', 'doi-asserted-by': 'crossref', 'first-page': '105430', 'DOI': '10.1016/j.antiviral.2022.105430', 'article-title': 'Combination Therapy with Nirmatrelvir and Molnupiravir Improves the ' 'Survival of SARS-CoV-2 Infected Mice', 'volume': '208', 'author': 'Jeong', 'year': '2022', 'journal-title': 'Antivir. Res.'}, { 'key': 'ref_17', 'doi-asserted-by': 'crossref', 'unstructured': 'Gidari, A., Sabbatini, S., Schiaroli, E., Bastianelli, S., Pierucci, S., ' 'Busti, C., Saraca, L.M., Capogrossi, L., Pasticci, M.B., and Francisci, ' 'D. (2023). Synergistic Activity of Remdesivir-Nirmatrelvir Combination ' 'on a SARS-CoV-2 In Vitro Model and a Case Report. Viruses, 15.', 'DOI': '10.3390/v15071577'}, { 'key': 'ref_18', 'doi-asserted-by': 'crossref', 'first-page': '623', 'DOI': '10.1080/1120009X.2023.2196917', 'article-title': 'Successful Treatment of Persistent SARS-CoV-2 Infection with ' 'Nirmatrelvir/Ritonavir plus Sotrovimab in Four Immunocompromised ' 'Patients', 'volume': '35', 'author': 'Lanzafame', 'year': '2023', 'journal-title': 'J. Chemother.'}, { 'key': 'ref_19', 'doi-asserted-by': 'crossref', 'first-page': '53', 'DOI': '10.1016/j.ijid.2023.04.412', 'article-title': 'Combination Regimen of Nirmatrelvir/Ritonavir and Molnupiravir for the ' 'Treatment of Persistent SARS-CoV-2 Infection: A Case Report and a ' 'Scoping Review of the Literature', 'volume': '133', 'author': 'Marangoni', 'year': '2023', 'journal-title': 'Int. J. Infect. Dis.'}, { 'key': 'ref_20', 'doi-asserted-by': 'crossref', 'first-page': '280', 'DOI': '10.1093/cid/ciad181', 'article-title': 'Triple Combination Therapy with 2 Antivirals and Monoclonal Antibodies ' 'for Persistent or Relapsed Severe Acute Respiratory Syndrome ' 'Coronavirus 2 Infection in Immunocompromised Patients', 'volume': '77', 'author': 'Mikulska', 'year': '2023', 'journal-title': 'Clin. Infect. Dis.'}, { 'key': 'ref_21', 'doi-asserted-by': 'crossref', 'first-page': '105429', 'DOI': '10.1016/j.antiviral.2022.105429', 'article-title': 'Generation of a VeroE6 Pgp Gene Knock out Cell Line and Its Use in ' 'SARS-CoV-2 Antiviral Study', 'volume': '208', 'author': 'Zhu', 'year': '2022', 'journal-title': 'Antivir. Res.'}, { 'key': 'ref_22', 'doi-asserted-by': 'crossref', 'unstructured': 'Fiaschi, L., Dragoni, F., Schiaroli, E., Bergna, A., Rossetti, B., ' 'Giammarino, F., Biba, C., Gidari, A., Lai, A., and Nencioni, C. (2022). ' 'Efficacy of Licensed Monoclonal Antibodies and Antiviral Agents against ' 'the SARS-CoV-2 Omicron Sublineages BA.1 and BA.2. Viruses, 14.', 'DOI': '10.20944/preprints202205.0381.v1'}, { 'key': 'ref_23', 'doi-asserted-by': 'crossref', 'first-page': '113683', 'DOI': '10.1016/j.ejmech.2021.113683', 'article-title': 'System-Oriented Optimization of Multi-Target 2,6-Diaminopurine ' 'Derivatives: Easily Accessible Broad-Spectrum Antivirals Active against ' 'Flaviviruses, Influenza Virus and SARS-CoV-2', 'volume': '224', 'author': 'Vicenti', 'year': '2021', 'journal-title': 'Eur. J. Med. Chem.'}, { 'key': 'ref_24', 'doi-asserted-by': 'crossref', 'first-page': 'W739', 'DOI': '10.1093/nar/gkac382', 'article-title': 'SynergyFinder 3.0: An Interactive Analysis and Consensus Interpretation ' 'of Multi-Drug Synergies across Multiple Samples', 'volume': '50', 'author': 'Ianevski', 'year': '2022', 'journal-title': 'Nucleic Acids Res.'}, { 'key': 'ref_25', 'doi-asserted-by': 'crossref', 'first-page': '504', 'DOI': '10.1016/j.csbj.2015.09.001', 'article-title': 'Searching for Drug Synergy in Complex Dose-Response Landscapes Using an ' 'Interaction Potency Model', 'volume': '13', 'author': 'Yadav', 'year': '2015', 'journal-title': 'Comput. Struct. Biotechnol. J.'}, { 'key': 'ref_26', 'doi-asserted-by': 'crossref', 'unstructured': 'Koszalka, P., Subbarao, K., and Baz, M. (2022). Preclinical and Clinical ' 'Developments for Combination Treatment of Influenza. PLoS Pathog., 18.', 'DOI': '10.1371/journal.ppat.1010481'}, { 'key': 'ref_27', 'doi-asserted-by': 'crossref', 'first-page': '726', 'DOI': '10.1111/fcp.12889', 'article-title': 'Viral Target and Metabolism-Based Rationale for Combined Use of ' 'Recently Authorized Small Molecule COVID-19 Medicines: Molnupiravir, ' 'Nirmatrelvir, and Remdesivir', 'volume': '37', 'author': 'Yan', 'year': '2023', 'journal-title': 'Fundam. Clin. Pharmacol.'}, { 'key': 'ref_28', 'doi-asserted-by': 'crossref', 'first-page': 'e28877', 'DOI': '10.1002/jmv.28877', 'article-title': 'SARS-CoV-2 Intrahost Evolution in Immunocompromised Patients in ' 'Comparison with Immunocompetent Populations after Treatment', 'volume': '95', 'author': 'Ahmadi', 'year': '2023', 'journal-title': 'J. Med. Virol.'}, { 'key': 'ref_29', 'doi-asserted-by': 'crossref', 'first-page': '342', 'DOI': '10.1093/cid/ciac769', 'article-title': 'Remdesivir Resistance in Transplant Recipients with Persistent ' 'Coronavirus Disease 2019', 'volume': '76', 'author': 'Hogan', 'year': '2023', 'journal-title': 'Clin. Infect. Dis.'}, { 'key': 'ref_30', 'doi-asserted-by': 'crossref', 'unstructured': 'Yang, S., Multani, A., Garrigues, J.M., Oh, M.S., Hemarajata, P., ' 'Burleson, T., Green, N.M., Oliai, C., Gaynor, P.T., and Beaird, O.E. ' '(2023). Transient SARS-CoV-2 RNA-Dependent RNA Polymerase Mutations ' 'after Remdesivir Treatment for Chronic COVID-19 in Two Transplant ' 'Recipients: Case Report and Intra-Host Viral Genomic Investigation. ' 'Microorganisms, 11.', 'DOI': '10.3390/microorganisms11082096'}, { 'key': 'ref_31', 'doi-asserted-by': 'crossref', 'unstructured': 'Zuckerman, N.S., Bucris, E., Keidar-Friedman, D., Amsalem, M., and ' 'Brosh-Nissimov, T. (2023). Nirmatrelvir Resistance-de Novo E166V/L50V ' 'Mutations in an Immunocompromised Patient Treated with Prolonged ' 'Nirmatrelvir/Ritonavir Monotherapy Leading to Clinical and Virological ' 'Treatment Failure—A Case Report. Clin. Infect. Dis., ciad494.', 'DOI': '10.1093/cid/ciad494'}, { 'key': 'ref_32', 'doi-asserted-by': 'crossref', 'first-page': '2193', 'DOI': '10.1016/S0140-6736(22)01938-9', 'article-title': 'WHO’s Therapeutics and COVID-19 Living Guideline on MAbs Needs to Be ' 'Reassessed', 'volume': '400', 'author': 'Wu', 'year': '2022', 'journal-title': 'Lancet'}, { 'key': 'ref_33', 'doi-asserted-by': 'crossref', 'first-page': 'e00149', 'DOI': '10.1002/prp2.149', 'article-title': 'Analysis of Drug Combinations: Current Methodological Landscape', 'volume': '3', 'author': 'Foucquier', 'year': '2015', 'journal-title': 'Pharmacol. Res. Perspect.'}, { 'key': 'ref_34', 'doi-asserted-by': 'crossref', 'unstructured': 'Fuentealba-Manosalva, O., Mansilla, M., Buelvas, N., Martin-Martin, A., ' 'Torres, C.G., and López-Muñoz, R.A. (2023). Mind the Curve: ' 'Dose-Response Fitting Biases the Synergy Scores across Software Used for ' 'Chemotherapy Combination Studies. Int. J. Mol. Sci., 24.', 'DOI': '10.3390/ijms24119705'}, { 'key': 'ref_35', 'doi-asserted-by': 'crossref', 'first-page': '4607', 'DOI': '10.1038/s41467-021-24789-z', 'article-title': 'MuSyC Is a Consensus Framework That Unifies Multi-Drug Synergy Metrics ' 'for Combinatorial Drug Discovery', 'volume': '12', 'author': 'Wooten', 'year': '2021', 'journal-title': 'Nat. Commun.'}, { 'key': 'ref_36', 'doi-asserted-by': 'crossref', 'unstructured': 'Plebani, R., Bai, H., Si, L., Li, J., Zhang, C., and Romano, M. (2022). ' '3D Lung Tissue Models for Studies on SARS-CoV-2 Pathophysiology and ' 'Therapeutics. Int. J. Mol. Sci., 23.', 'DOI': '10.3390/ijms231710071'}, { 'key': 'ref_37', 'doi-asserted-by': 'crossref', 'first-page': '105345', 'DOI': '10.1016/j.antiviral.2022.105345', 'article-title': 'Animal models for studying coronavirus infections and developing ' 'antiviral agents and vaccines', 'volume': '203', 'author': 'Lin', 'year': '2022', 'journal-title': 'Antivir. Res.'}], 'container-title': 'Viruses', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://www.mdpi.com/1999-4915/16/2/168/pdf', 'content-type': 'unspecified', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2024, 1, 23]], 'date-time': '2024-01-23T12:54:30Z', 'timestamp': 1706014470000}, 'score': 1, 'resource': {'primary': {'URL': 'https://www.mdpi.com/1999-4915/16/2/168'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2024, 1, 23]]}, 'references-count': 37, 'journal-issue': {'issue': '2', 'published-online': {'date-parts': [[2024, 2]]}}, 'alternative-id': ['v16020168'], 'URL': 'http://dx.doi.org/10.3390/v16020168', 'relation': {}, 'ISSN': ['1999-4915'], 'subject': ['Virology', 'Infectious Diseases'], 'container-title-short': 'Viruses', 'published': {'date-parts': [[2024, 1, 23]]}}
Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.
  or use drag and drop   
Submit