A viral RNA-dependent RNA polymerase inhibitor VV116 broadly inhibits human coronaviruses and has synergistic potency with 3CLpro inhibitor nirmatrelvir

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Sept. 22, 2023

Abstract During the ongoing pandemic, providing treatment consisting of effective, low-cost oral antiviral drugs at an early stage SARS-CoV-2 infection has been a priority for controlling COVID-19. Although Paxlovid and molnupiravir have received emergency approval from FDA, some side effect concerns emerged, possible agents are still limited, resulting in optimized drug development becoming urgent requirement. An remdesivir derivative, VV116, reported to promising effects against positive therapeutic outcomes clinical trials. However, whether VV116 broad-spectrum anti-coronavirus activity potential synergy with other is not clear. Here, we uncovered potency variants concern (VOCs), HCoV-OC43, HCoV-229E various cell lines. In vitro combination screening targeted RdRp proteinase, highlighting synergistic nirmatrelvir on HCoV-OC43 SARS-CoV-2. When co-administrated ritonavir, showed significantly enhanced noninteracting pharmacokinetic properties mice. Our findings will facilitate or VV116+nirmatrelvir fight coronavirus infection.

Language: Английский

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Immunobiology of COVID-19: Mechanistic and therapeutic insights from animal models

动物学研究, Journal Year: 2024, Volume and Issue: 45(4), P. 747 - 766

Published: Jan. 1, 2024

The distribution of the immune system throughout body complicates

Language: Английский

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Structure-Based Optimization of Pyridone α-Ketoamides as Inhibitors of the SARS-CoV-2 Main Protease

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 16, 2025

The main protease Mpro is a clinically validated target to treat infections by the coronavirus SARS-CoV-2. Among first reported inhibitors was peptidomimetic α-ketoamide 13b, whose cocrystal structure with paved way for multiple lead-finding studies. We established structure-activity relationships 13b series modifying residues at P1', P3, and P4 sites. Guided structures, we reduced P1' substituent size better fill pocket added fluorine pyridone ring, enabling new hydrogen bond Gln189 in P3. 22 novel analogues, 6d 12d inhibited IC50s of 110 nM 40 nM, improving potency up 9.5-fold. Compound had pronounced antiviral activity an EC50 1.6 μM stable plasma microsomes. study illustrates potential structure-based design systematically improve α-ketoamides.

Language: Английский

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The effect of molnupiravir and nirmatrelvir on SARS-CoV-2 genome diversity in severe models of COVID-19

Microbiology Spectrum, Journal Year: 2025, Volume and Issue: unknown

Published: March 25, 2025

ABSTRACT Immunocompromised individuals are susceptible to severe coronavirus disease 2019 and potentially contribute the emergence of variants with altered pathogenicity due persistent infection. This study investigated impact immunosuppression on acute respiratory syndrome 2 (SARS-CoV-2) infection in K18-hACE2 mice effectiveness antiviral treatments this context during first 7 days Mice were immunosuppressed using cyclophosphamide infected a B lineage SARS-CoV-2. Molnupiravir nirmatrelvir, alone combination, administered, viral load sequence diversity assessed. Treatment but immunocompromised both compounds either singly or combination resulted decreased loads pathological changes compared untreated animals. also abrogated neuronal tissue. However, no consistent consensus observed, except for S:H655Y mutation. Molnupiravir, not nirmatrelvir alone, increased transition/transversion ratio, representative G > A C U mutations, increase was by co-administration molnupiravir. Notably, itself did appear promote mutational characteristics concern (VOCs). Further investigations warranted fully understand role VOC development, especially taking persistence into consideration, inform optimized public health strategies. It is more likely that immunodeficiency promotes does necessarily lead substantial consensus-level absence selection pressure. Consistent mechanisms action, molnupiravir showed stronger mutagenic effect than model. IMPORTANCE The central aim risk-assess administering compound, molnupiravir, patients believed already be at risk generating diversity, which could have implications resistance development. Combination therapy has long history mitigating used demonstrate its potential usefulness context. Animals treated an ratios over time, drug’s mechanism action recent UK-wide phase II clinical trial assessing efficacy humans. addition clearance, turn reduces probability rapid intra-host evolution

Language: Английский

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Impact of Red Sea Bream Iridovirus Infection on Rock Bream (Oplegnathus fasciatus) and Other Fish Species: A Study of Horizontal Transmission

Animals, Journal Year: 2023, Volume and Issue: 13(7), P. 1210 - 1210

Published: March 30, 2023

Red sea bream iridovirus (RSIV) causes significant economic losses in aquaculture. Here, we analyzed the pathogenicity, viral shedding, and transmission dynamics of RSIV rock (Oplegnathus fasciatus) by employing immersion infection cohabitation challenge models. Rock challenged exposure exhibited 100% mortality within 35 days post exposure, indicating that shedding seawater peaked after mortality. At 25 °C, a positive correlation between loads infected virus into was observed. Specific lesions were observed spleen kidney bream, load had highest with histopathological grade. A mimicking natural conditions performed to assess determine pathogenicity load. The RSIV-infected breams (donors) cohabited uninfected red (Pagrus major), flathead grey mullet (Mugil cephalus) (recipients) at both °C 15 °C. In group maintained no across all experimental groups. However, detected recipient fish. Our results provide preliminary data for further epidemiological analyses aid development preventive measures management RSIVD

Language: Английский

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