The Antiviral Mechanism of Action of Molnupiravir in Humans with COVID-19 DOI Creative Commons
Timothy P. Sheahan, Laura J. Stevens, Tara M. Narowski

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 27, 2023

Abstract Meaningful metrics of antiviral activity are essential for determining the efficacy therapeutics in human clinical trials. Molnupiravir (MOV) is a broadly acting nucleoside analog prodrug that acts as competitive alternative substrate SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). We developed an assay, Culture-PCR, to better understand impact MOV therapy on infectious SARS-CoV-2. Culture-PCR revealed eliminated virus within 48 hours nasopharyngeal compartment, upper airway location with greatest levels virus. was associated increases mutations across viral genome but select regions were completely unaffected, thus identifying where mutation likely abrogates infectivity. did not alter magnitude or neutralization capacity humoral immune response, documented correlate protection. Thus, we provide holistic insights into function adults COVID-19.

Language: Английский

The evolution of SARS-CoV-2 DOI Open Access
Peter V. Markov, Mahan Ghafari, Martin Beer

et al.

Nature Reviews Microbiology, Journal Year: 2023, Volume and Issue: 21(6), P. 361 - 379

Published: April 5, 2023

Language: Английский

Citations

768
The host-targeted antiviral drug Zapnometinib exhibits a high barrier to the development of SARS-CoV-2 resistance DOI Creative Commons
André Schreiber, Franziska Rodner,

Nicole Oberberg

et al.

Antiviral Research, Journal Year: 2024, Volume and Issue: 225, P. 105840 - 105840

Published: March 2, 2024

Host targeting antiviral drugs (HTA) are directed against cellular mechanisms which can be exploited by viruses. These essential for viral replication, because missing functions cannot compensated the virus. However, this assumption needs experimental proof. Here we compared HTA Zapnometinib (ZMN), with direct acting antivirals (DAA) (Remdesivir (RDV), Molnupiravir (MPV), Nirmatrelvir (NTV), Ritonavir (RTV), Paxlovid PAX)), in terms of their potency to induce reduced drug susceptibilities SARS-CoV-2. During serial passage δ-B1.617.2 adaptation all DAAs occurred, while inhibitory capacity ZMN was not altered. Known single nucleotide polymorphisms (SNPs) responsible partial resistances were found RDV, NTV and PAX. Additionally, high mutagenic potential MPV confirmed decreased efficacies first time. Reduced DAA efficacy did alter ZMN. results show that confers a barrier towards development resistance has act partially DAA-insensitive

Language: Английский

Citations

8
Antiviral combination therapies for persistent COVID-19 in immunocompromised patients DOI Creative Commons
Daniele Focosi, Fabrizio Maggi, Alessandra D’Abramo

et al.

International Journal of Infectious Diseases, Journal Year: 2023, Volume and Issue: 137, P. 55 - 59

Published: Sept. 30, 2023

After the third year of COVID-19 pandemic, most severe burden falls upon immunocompromised patients who cannot mount an endogenous immune response after both vaccination and/or natural infection. They also experience persistent SARS-CoV-2 infection with high viral loads often unsuccessfully managed by standard antiviral monotherapy regimen initially validated for treatment immunocompetent patients, only. The off-label prescription such regimens in is likely to drive emergence treatment-related escape, relapses, excess morbidity, and mortality from delayed underlying disorders. A possible approach mitigate consequence based on combined therapies.

Language: Английский

Citations

17
Early initiation of combined therapy in severely immunocompromised patients with COVID-19: a retrospective cohort study DOI Creative Commons
Salvatore Rotundo,

Lavinia Berardelli,

Sara Palma Gullì

et al.

BMC Infectious Diseases, Journal Year: 2024, Volume and Issue: 24(1)

Published: June 6, 2024

Abstract This single-centre retrospective cohort study reports on the results of a descriptive (non-comparative) early initiation antivirals and combined monoclonal antibody therapy (mAbs) in 48 severely immunocompromised patients with COVID-19. The assessed outcomes duration viral shedding. started (ECT) median 2 days (interquartile range [IQR]: 1–3 days) after diagnosis SARS-CoV-2 infection. Except for 1 patient who died due COVID-19-related respiratory failure, had their first negative nasopharyngeal swab result 11 (IQR: 6–17 starting therapy. There were no severe side effects. During follow-up period 512 413–575 days), 6 (12.5%) 16 (33.3%) admitted to hospital. Moreover, 12 (25%) diagnosed reinfection 245 138–401 treatment. No relapses reported. Although there was comparison group, these compare favourably COVID-19 reported literature.

Language: Английский

Citations

6
COVID drug drives viral mutations — and now some want to halt its use DOI

Ewen Callaway

Nature, Journal Year: 2023, Volume and Issue: 614(7948), P. 399 - 399

Published: Feb. 7, 2023

Language: Английский

Citations

14
Discovery of C-Linked Nucleoside Analogues with Antiviral Activity against SARS-CoV-2 DOI
Eugen F. Mesaros, Benjamin J. Dugan, Min Gao

et al.

ACS Infectious Diseases, Journal Year: 2024, Volume and Issue: 10(5), P. 1780 - 1792

Published: April 23, 2024

The recent COVID-19 pandemic underscored the limitations of currently available direct-acting antiviral treatments against acute respiratory RNA-viral infections and stimulated major research initiatives targeting anticoronavirus agents. Two novel nsp5 protease (MPro) inhibitors have been approved, nirmatrelvir ensitrelvir, along with two existing nucleos(t)ide analogues repurposed as nsp12 polymerase inhibitors, remdesivir molnupiravir, but a need still exists for therapies improved potency systemic exposure oral dosing, better metabolic stability, reduced resistance toxicity risks. Herein, we summarize our toward identifying that led to nucleoside 10e 10n, which showed favorable pan-coronavirus activity in cell-infection screens, were metabolized active triphosphate nucleotides cell-incubation studies, demonstrated target (nsp12) engagement biochemical assays.

Language: Английский

Citations

5
Oral Bemnifosbuvir (AT-527) Vs Placebo in Patients With mild-to-moderate COVID-19 in an Outpatient Setting (MORNINGSKY) DOI Creative Commons

Arantxa Horga,

Rebecca Saenz,

Gürdal Yılmaz

et al.

Future Virology, Journal Year: 2023, Volume and Issue: 18(13), P. 839 - 853

Published: Sept. 1, 2023

This phase III study assessed the efficacy/safety/antiviral activity/pharmacokinetics of bemnifosbuvir, a novel, oral nucleotide analog to treat COVID-19.

Language: Английский

Citations

9
Phase II Study of Bemnifosbuvir in High-Risk Participants in a Hospital Setting with Moderate COVID-19 DOI Creative Commons

Arantxa Horga,

Daniel R. Kuritzkes, John J. Kowalczyk

et al.

Future Virology, Journal Year: 2023, Volume and Issue: 18(8), P. 489 - 500

Published: June 1, 2023

Bemnifosbuvir, a novel, oral, nonmutagenic, nonteratogenic nucleotide analogue inhibits SARS-CoV-2 replication in vitro.Adults hospital settings with moderate COVID-19 were randomized 1:1 bemnifosbuvir/placebo. Study amended to two parts after interim analysis; part B enrollment limited owing evolving standard of care.Although the study ended early and did not meet primary efficacy end point, bemnifosbuvir was well tolerated contribute all-cause mortality. Compared placebo, treatment resulted 0.61 log10 greater viral load mean change on day 2; trend sustained through 8. Treatment-emergent adverse events similar both groups; most mild/moderate, unrelated drug.Our results suggest potential role for blunting progression.NCT04396106 (ClinicalTrials.gov).

Language: Английский

Citations

7
Factors in Determining the Chemo-Selective Reactions at Thymine in One-Electron Oxidation of DNA: Identification of an Intramolecular Proton Coupled Electron Transfer Pathway via a Full-Carbon Spin Centre Shift DOI Creative Commons
Liuqun Gu

Published: Jan. 3, 2024

Oxidation of DNA causes chemical reactions at nucleobase that ultimately result in damage via mutation. The reaction site could prefer thymine through one-electron oxidation “guanine poor regions” or the presence Cu(II) with guanine. Two competitive processes H2O/O2 addition to radical cation C5-C6 double bond and a proton loss proton-coupled electron transfer (PCET) methyl group were proposed for elucidation complex mechanism thymine. repairability mutation resulted by latter process is uncertain, factors determining divergent pathways are not yet clear. A future better understanding great need managing possible stress caused perinatal carcinogenic side effects thymine-containing drug Azidothymidine (AZT), rational design new anti-virus drugs covid-19 treatment case Molnupiravir-mutated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses high proportion G-to-A C-to-T mutations evolves into dominant variant. systematic study photocatalyzed thymine/thymidine reactions, hydration pyrimidines, direct β-alkylation aldehydes/ketones photoredox organocatalysis, C-H functionalization indole benzylic sp3 carbon photocatalysis, photo-induced sugar transformations spin-centre shift (SCS) was carried out evaluate role water, ions functional groups. Non-nucleophilic anions found play an essential favoring PCET pathway as excellent hydrogen acceptor. Systematic experimental evidences support “build-in amine catalysis” intramolecular full-carbon SCS, alternative direction carbonyl water wire-mediated also identified. bioinspired SCS assistance acetate anion migration explaining unique “5πe−carbonyl activation mode” organocatalysis. demonstrated both biomimetic general mode named “Radical Cation Induced Addition (RCIA)” toward catalytic asymmetric hydration, transient-metal-free indoles, would be feasible similar mechanism.

Language: Английский

Citations

2
Management of SARS-CoV-2 and Persistent Viral Detection in Solid Organ Transplant Recipients DOI Creative Commons

Karen Larissa Pereira de Castro,

Chetan Naik,

Cedric W. Spak

et al.

Current Pulmonology Reports, Journal Year: 2024, Volume and Issue: 13(1), P. 26 - 37

Published: Feb. 24, 2024

Abstract Purpose of Review We explore the challenges managing solid organ transplant recipients (SOTRs) during COVID-19 pandemic, with a focus on prolonged viral detection in immunosuppressed individuals. Recent Findings SOTR guidelines recommend three mRNA vaccine doses additional booster dosing and continued protective post-vaccination measures. therapies are similar for SOTRs non-SOTRs, although drug-drug interactions limit use some such as nirmatrelvir/ritonavir (NIM-RTV). Inpatient treatment options include remdesivir steroids; outpatient antiviral NIM-RTV or remdesivir. Whereas molnupiravir has not been withdrawn USA, it is no longer available Europe due to safety efficacy concerns, along selection mutagenesis. Prolonged replication patients presents risk future variant generation concern transmission. Summary emphasize vaccination measures; persistently positive cases remain challenge. Medications promoting mutagenesis ill-advised those already at incubating variants capable immunologic escape.

Language: Английский

Citations

1