The problem of SARS-CoV-2 virus resistance to direct-acting antivirals DOI Creative Commons
Е. Л. Гасич, Е. Н. Кроткова, A. D. Kasko

et al.

Biological Products Prevention Diagnosis Treatment, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 12, 2024

INTRODUCTION. The high prevalence of mutations in the SARS-CoV-2 genome raises particular concerns about resistance virus to current antiviral therapy, including inhibitors main protease, or 3C-like protease (3CLpro), and RNA-dependent RNA polymerase (RdRp). AIM. This study aimed analyse prevalence, spectrum, causes conferring approved pipeline RdRp 3CLpro on basis clinical, virological, genotypic data. DISCUSSION. authors have analysed antivirals (RdRp inhibitors, remdesivir molnupiravir, paxlovid) 2021–2024. results suggest that certain existed prior use these antivirals. resistance-conferring does not exceed 0.5% global population. However, clinical experimental studies demonstrate possibility a more than 200-fold reduction susceptibility medicinal products and, particular, emergence multidrug-resistant variants. is especially important for immunocompromised patients. can persist such patients many months, during which spontaneous selection-driven render therapy ineffective. would create risk spreading drug-resistant variants and/or adverse outcomes CONCLUSIONS. As COVID-19 treatment coverage increases, there may be rise virus. presented data indicate need genomic epidemiological surveillance, an analysis potential targets based observations. In future, surveillance determine strategy develop new inhibitors) adjusted resistant

Language: Английский

Sequential intrahost evolution and onward transmission of SARS-CoV-2 variants DOI Creative Commons
Ana S. González-Reiche, Hala Alshammary, Sarah Schaefer

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: June 3, 2023

Abstract Persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have been reported in immune-compromised individuals and people undergoing immune-modulatory treatments. Although intrahost evolution has documented, direct evidence of subsequent transmission continued stepwise adaptation is lacking. Here we describe sequential persistent SARS-CoV-2 three that led to the emergence, forward transmission, a new Omicron sublineage, BA.1.23, over an eight-month period. The initially transmitted BA.1.23 variant encoded seven additional amino acid substitutions within spike protein (E96D, R346T, L455W, K458M, A484V, H681R, A688V), displayed substantial resistance neutralization by sera from boosted and/or BA.1-infected study participants. Subsequent replication resulted (S254F, N448S, F456L, M458K, F981L, S982L) as well five other virus proteins. Our findings demonstrate not only BA.1 lineage can diverge further its already exceptionally mutated genome but also patients with transmit these viral variants. Thus, there is, urgent need implement strategies prevent prolonged limit spread newly emerging, neutralization-resistant variants vulnerable patients.

Language: Английский

Citations

65
Multidrug-resistant mutations to antiviral and antibody therapy in an immunocompromised patient infected with SARS-CoV-2 DOI Creative Commons
Yosuke Hirotsu, Hiroaki Kobayashi,

Yumiko Kakizaki

et al.

Med, Journal Year: 2023, Volume and Issue: 4(11), P. 813 - 824.e4

Published: Sept. 7, 2023

Antiviral and antibody therapies for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are being recommended high-risk patients, but the potential development of multidrug-resistant mutations in immunocompromised patients is unclear.To investigate treatment course cases prolonged viral shedding an patient with SARS-CoV-2 infection, we conducted longitudinal measurements laboratory tests, chest computed tomography (CT) image evaluations, titers, antigen levels nasopharyngeal swabs. Furthermore, performed whole-genome sequencing digital PCR analysis to examine mechanisms drug resistance.We present a case 65-year-old man history malignant lymphoma who was treated multiple antiviral therapies, including sotrovimab, remdesivir, paxlovid (nirmatrelvir/ritonavir), molnupiravir. Initially, decreased after treatments. However, virus rebounded, showed no virologic response. The genome revealed single Omicron subvariant (BA.1.1), which evolved within host during disease progression. viruses had acquired resistance nirmatrelvir (3 chymotrypsin-like protease [3CLpro] E166 A/V), sotrovimab (spike P337L E340K), remdesivir (RNA-dependent RNA polymerase [RdRp] V166L).Our results indicate that survival fitness persist infected subpopulation selection pressure.This study supported by JSPS KAKENHI Early-Career Scientists 18K16292 (Y.H.), Grant-in-Aid Scientific Research (B) 20H03668 23H02955 YASUDA Medical Foundation Uehara Memorial Takeda Science Kato Bioscience (Y.H.).

Language: Английский

Citations

51
Remdesivir: A Review in COVID-19 DOI Creative Commons

Hannah A. Blair

Drugs, Journal Year: 2023, Volume and Issue: 83(13), P. 1215 - 1237

Published: Aug. 17, 2023

Remdesivir (Veklury®), a nucleotide analogue prodrug with broad-spectrum antiviral activity, is approved for the treatment of coronavirus disease 2019 (COVID-19), illness caused by severe acute respiratory syndrome 2 infection. Unlike some antivirals, remdesivir has low potential drug-drug interactions. In pivotal ACTT-1 trial in hospitalized patients COVID-19, daily intravenous infusions significantly reduced time to recovery relative placebo. Subsequent trials provided additional support efficacy moderate or greater benefit seen minimal oxygen requirements at baseline. Clinical also demonstrated other patient populations, including outpatients high risk progression as well paediatric patients. terms mortality, results were equivocal. However, appeared have small mortality who not already being ventilated was generally tolerated clinical trials, but pharmacovigilance data found an increased hepatic, renal and cardiovascular adverse drug reactions real-world setting. conclusion, represents useful option particularly those require supplemental oxygen. Coronavirus (COVID-19) first reported China quickly spread around world. The symptoms COVID-19 can vary from person person, people having no others becoming very unwell. Most treat their home, may be admitted hospital and/or treated specialized medications such (Veklury®). medicine that reduce amount virus causes COVID-19. It given once day, usually 5–10 days, infusion. been shown improve children adolescents. death are before they start treatment. A 3-day course effective whose age underlying health puts them severely ill. tolerated. Therefore, especially

Language: Английский

Citations

35
In vitro and in vivo characterization of SARS-CoV-2 strains resistant to nirmatrelvir DOI Creative Commons
Maki Kiso, Yuri Furusawa, Ryuta Uraki

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: July 4, 2023

Nirmatrelvir, an oral antiviral agent that targets a SARS-CoV-2 main protease (3CLpro), is clinically useful against infection with including its omicron variants. Since most subvariants have reduced sensitivity to many monoclonal antibody therapies, potential resistance nirmatrelvir major public health concern. Several amino acid substitutions been identified as being responsible for susceptibility nirmatrelvir. Among them, we selected L50F/E166V and L50F/E166A/L167F in the 3CLpro because these combinations of are unlikely affect virus fitness. We prepared characterized delta variants possessing Nsp5-L50F/E166V Nsp5-L50F/E166A/L167F. Both mutant viruses showed decreased their growth VeroE6/TMPRSS2 cells was delayed. attenuated phenotypes male hamster model, maintained airborne transmissibility, were outcompeted by wild-type co-infection experiments absence nirmatrelvir, but less so presence drug. These results suggest Nsp5-L50F/E166A/L167F do not become dominant nature. However, it important closely monitor emergence nirmatrelvir-resistant resistant additional compensatory mutations could emerge, outcompete virus, dominant.

Language: Английский

Citations

31
SARS-CoV-2 resistance to monoclonal antibodies and small-molecule drugs DOI Creative Commons
Sho Iketani, David D. Ho

Cell chemical biology, Journal Year: 2024, Volume and Issue: 31(4), P. 632 - 657

Published: April 1, 2024

Over four years have passed since the beginning of COVID-19 pandemic. The scientific response has been rapid and effective, with many therapeutic monoclonal antibodies small molecules developed for clinical use. However, given ability viruses to become resistant antivirals, it is perhaps no surprise that field identified resistance nearly all these compounds. Here, we provide a comprehensive review profile each therapeutics. We hope this resource provides an atlas mutations be aware agent, particularly as springboard considerations next generation antivirals. Finally, discuss outlook thoughts moving forward in how continue manage this, next,

Language: Английский

Citations

10
Combinations of Host- and Virus-Targeting Antiviral Drugs Confer Synergistic Suppression of SARS-CoV-2 DOI Creative Commons

Jessica Wagoner,

Shawn Herring,

Tien-Ying Hsiang

et al.

Microbiology Spectrum, Journal Year: 2022, Volume and Issue: 10(5)

Published: Oct. 3, 2022

Imagine a future viral pandemic where if you test positive for the new virus, can quickly take some medicines at home few days so that do not get too sick. To date, only single drugs have been approved outpatient use against SARS-CoV-2, and we are learning these limitations may succumb to drug resistance.

Language: Английский

Citations

36
Viral Resistance Analyses From the Remdesivir Phase 3 Adaptive COVID-19 Treatment Trial-1 (ACTT-1) DOI Creative Commons
Charlotte Hedskog, Lauren Rodriguez, Pavitra Roychoudhury

et al.

The Journal of Infectious Diseases, Journal Year: 2023, Volume and Issue: 228(9), P. 1263 - 1273

Published: July 19, 2023

Abstract Background Remdesivir is approved for treatment of coronavirus disease 2019 (COVID-19) in nonhospitalized and hospitalized adult pediatric patients. Here we present severe acute respiratory syndrome 2 (SARS-CoV-2) resistance analyses from the phase 3 ACTT-1 randomized placebo-controlled trial conducted participants with COVID-19. Methods Swab samples were collected at baseline longitudinally through day 29. SARS-CoV-2 genomes sequenced using next-generation sequencing. Phenotypic analysis was directly on participant virus isolates and/or subgenomic replicons expressing mutations identified Nsp12 target gene. Results Among both postbaseline sequencing data, emergent substitutions observed 12 31 (38.7%) 30 (40.0%) remdesivir placebo arms, respectively. No arm more than 1 participant. Phenotyping showed low to no change susceptibility relative wild-type reference tested: A16V (0.8-fold EC50), P323L + V792I (2.2-fold), C799F (2.5-fold), K59N (1.0-fold), (3.4-fold). Conclusions The similar rate emerging arms minimal among tested support a high barrier development COVID-19 Clinical Trials Registration. NCT04280705.

Language: Английский

Citations

17
Emergence of SARS-CoV-2 with Dual-Drug Resistant Mutations During a Long-Term Infection in a Kidney Transplant Recipient DOI Creative Commons
Yoko Tanino,

Keisuke Nishioka,

Chie Yamamoto

et al.

Infection and Drug Resistance, Journal Year: 2024, Volume and Issue: Volume 17, P. 531 - 541

Published: Feb. 1, 2024

Introduction: Various therapeutic agents are being developed for the treatment of coronavirus disease 2019 (COVID-19). Therefore, it is crucial to accumulate information regarding features drug-resistant viruses these antiviral drugs. Methods: We investigated emergence dual-drug resistance in a kidney transplant recipient who received sotrovimab (from day 0) and remdesivir (RDV) 8 17). sequenced whole viral genomes from nasopharyngeal swabs taken on 0 seven points after starting (on days 12, 19, 23, 37, 43, 48, 58). The genetic traits wild-type (day descendant (after 12) were determined by comparing with those Wuhan strain strain, respectively. Three isolates samples collected 0, 37) their escape ability growth kinetics vitro. Results: resistant mutation (S:E340K) RDV RdRp:V792I (nt: G15814A) emerged within 12 11 19) treatment, 23 isolate harboring S:E340K/RdRp:V791I was both RDV, showing 364- 2.73-fold higher respectively, compared wild-type. Moreover, isolate, 37 accumulated multiple additional mutations had level Conclusion: Drug-resistant variants double (S:E340K/RdRp:V791I) became dominant suggesting that even combination therapy involving may emerge rapidly immunocompromised patients. dual-resistant lower virus yields than vitro, they paid fitness cost. Keywords: SARS-CoV-2, sotrovimab, remdesivir, drug resistance, immunosuppression

Language: Английский

Citations

7
A mutation in the coronavirus nsp13-helicase impairs enzymatic activity and confers partial remdesivir resistance DOI Creative Commons
Samantha L. Grimes, Young Joo Choi,

Anoosha Banerjee

et al.

mBio, Journal Year: 2023, Volume and Issue: unknown

Published: June 20, 2023

ABSTRACT Coronaviruses (CoVs) encode nonstructural proteins 1–16 (nsps 1–16) which form replicase complexes that mediate viral RNA synthesis. Remdesivir (RDV) is an adenosine nucleoside analog antiviral inhibits CoV RDV resistance mutations have been reported only in the protein 12 RNA-dependent polymerase (nsp12-RdRp). We here show a substitution mutation nsp13-helicase (nsp13-HEL A335V) of betacoronavirus murine hepatitis virus (MHV) was selected during passage with parent compound confers partial independently and additively when expressed co-selected nsp12-RdRp. The MHV A335V did not enhance replication or competitive fitness compared to WT remained sensitive active cytidine molnupiravir (MOV). Biochemical analysis SARS-CoV-2 helicase encoding homologous (A336V) demonstrates mutant retained ability associate core nsps 7, 8, but had impaired unwinding ATPase activity. Together, these data identify novel determinant nsp13-HEL enzymatic activity, define new genetic pathway for resistance, demonstrate importance surveillance testing arise genomes. IMPORTANCE Despite development effective vaccines against COVID-19, continued circulation emergence variants support need antivirals such as RDV. Understanding pathways essential emerging variants, combination therapies, identifying potential targets inhibition. also impairs functions, supporting studying individual cooperative functions 7–16 has GISAID database genomes, highlighting helicase.

Language: Английский

Citations

14
Substitutions in SARS-CoV-2 Mpro Selected by Protease Inhibitor Boceprevir Confer Resistance to Nirmatrelvir DOI Creative Commons
Karen Anbro Gammeltoft, Yuyong Zhou, Line A. Ryberg

et al.

Viruses, Journal Year: 2023, Volume and Issue: 15(9), P. 1970 - 1970

Published: Sept. 21, 2023

Nirmatrelvir, which targets the SARS-CoV-2 main protease (Mpro), is first-in-line drug for prevention and treatment of severe COVID-19, additional Mpro inhibitors are in development. However, risk resistance development threatens future efficacy such direct-acting antivirals. To gain knowledge on viral correlates to inhibitors, we selected resistant under with nirmatrelvir-related inhibitor boceprevir. during five escape experiments VeroE6 cells showed cross-resistance nirmatrelvir up 7.3-fold increased half-maximal effective concentration compared original SARS-CoV-2, determined concentration–response experiments. Sequence analysis revealed that viruses harbored substitutions L50F A173V. For reverse genetic studies, these were introduced into a cell-culture-infectious clone. Infectivity titration stability cell-culture-derived engineered mutants rescued fitness cost conferred by In experiments, A173V was driver boceprevir nirmatrelvir. Structural suggested can cause making binding less favorable. This study contributes comprehensive overview profile COVID-19 thus inform population monitoring contribute pandemic preparedness.

Language: Английский

Citations

13