Combination therapy with nirmatrelvir and molnupiravir improves the survival of SARS-CoV-2 infected mice

Jeong, Ju Hwan; Chokkakula, Santosh; Min, Seong Cheol; Kim, Beom Kyu; Choi, Won-Suk; Oh, Sol; Yun, Yu Soo; Kang, Da Hyeon; Lee, Ok-Jun; Kim, Eung‐Gook; Choi, Jang‐Hoon; Lee, Joo-Yeon; Choi, Young Ki; Baek, Yun Hee; Song, Min‐Suk

doi:10.1016/j.antiviral.2022.105430

Cited by 62 publications

(53 citation statements)

References 41 publications

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“…As the modes of action for MK-4482 and PF-07321332 are distinct, a combined therapy is potentially beneficial over monotherapy. This was supported by recent in vitro data demonstrating a synergistic antiviral effect of MK-4482 and PF-07321332 against Delta and Omicron VOCs in comparison with individual drug treatment ( 27 , 28 ) and by in vivo data for a Korean strain isolated early in the pandemic ( 29 ) using a transgenic mouse model ( 30 ). In our present study, combined administration of MK-4482 and PF-07321332 treatment in the rhesus macaque model was well tolerated as indicated by clinical observation and blood chemistry/hematology analyses showing no indication for adverse reaction.…”

Section: Discussionmentioning

confidence: 54%

Combined molnupiravir-nirmatrelvir treatment improves the inhibitory effect on SARS-CoV-2 in macaques

Rosenke¹,

Lewis²,

Feldmann³

et al. 2023

JCI Insight

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The periodic emergence of SARS-CoV-2 variants of concern (VOCs) with unpredictable clinical severity and ability to escape preexisting immunity emphasizes the continued need for antiviral interventions. Two small molecule inhibitors, molnupiravir (MK-4482), a nucleoside analog, and nirmatrelvir (PF-07321332), a 3C-like protease inhibitor, have recently been approved as monotherapy for use in high risk COVID-19 patients. As preclinical data are only available for rodent and ferret models, we here assessed the efficacy of MK-4482 and PF-07321332 alone and in combination against infection with the SARS-CoV-2 Delta VOC in the rhesus macaque COVID-19 model. Macaques were infected with the SARS-CoV-2 Delta variant and treated with either vehicle, MK-4482, PF-07321332 or a combination of MK-4482 and PF-07321332. Clinical exams were performed at 1, 2 and 4dpi to assess disease and virological parameters. Notably, use of MK-4482 and PF-07321332 in combination improved the individual inhibitory effect of both drugs resulting in milder disease progression, stronger reduction of virus shedding from mucosal tissues of the upper respiratory tract, stronger reduction of viral replication in the lower respiratory tract, and reduced lung pathology. Our data strongly indicate superiority of combined MK-4482 and PF-07321332 treatment of SARS-CoV-2 infections as demonstrated in the closest COVID-19 surrogate model.

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Section: Discussionmentioning

confidence: 54%

Combined molnupiravir-nirmatrelvir treatment improves the inhibitory effect on SARS-CoV-2 in macaques

Rosenke¹,

Lewis²,

Feldmann³

et al. 2023

JCI Insight

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“…In a study conducted by Jeong et al, the combination of molnupiravir and remdesivir led to a moderate improvement in survival rates of infected mice, while the combination of molnupiravir and nirmatrelvir resulted in a significant improvement in survival rates up to 80%. These findings suggest that the combination of molnupiravir with certain other drugs may have a synergistic effect, meaning that the combination is more effective at reducing the severity of the disease than either drug alone [ 80 ].…”

Section: Impact Of Molnupiravir On Sars-cov-2 Variantsmentioning

confidence: 99%

Molnupiravir: A Versatile Prodrug against SARS-CoV-2 Variants

et al. 2023

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The nucleoside analog β-D-N4-hydroxycytidine is the active metabolite of the prodrug molnupiravir and is accepted as an efficient drug against COVID-19. Molnupiravir targets the RNA-dependent RNA polymerase (RdRp) enzyme, which is responsible for replicating the viral genome during the replication process of certain types of viruses. It works by disrupting the normal function of the RdRp enzyme, causing it to make mistakes during the replication of the viral genome. These mistakes can prevent the viral RNA from being transcribed, converted into a complementary DNA template, translated, or converted into a functional protein. By disrupting these crucial steps in the viral replication process, molnupiravir can effectively inhibit the replication of the virus and reduce its ability to cause disease. This review article sheds light on the impact of molnupiravir and its metabolite on SARS-CoV-2 variants of concern, such as delta, omicron, and hybrid/recombinant variants. The detailed mechanism and molecular interactions using molecular docking and dynamics have also been covered. The safety and tolerability of molnupiravir in patients with comorbidities have also been emphasized.

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“…For SARS-CoV-2, possible combinations include nirmatrelvir with either molnupiravir or remdesivir. A study has shown improvement in survival of SARS-CoV-2 infected mice under such experimental combination therapies ( Jeong et al, 2022 ), but clinical data are needed. Co-administration of these drugs could synergize some adverse drug reactions.…”

Section: Sars-cov-2 and Antiviral Therapymentioning

confidence: 99%