Combinations of Host- and Virus-Targeting Antiviral Drugs Confer Synergistic Suppression of SARS-CoV-2.
Combinations of Host- and Virus-Targeting Antiviral Drugs Confer Synergistic Suppression of SARS-CoV-2.
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DOI：
10.1128/spectrum.03331-22
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发表时间：
2022-10-26
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
在临床试验中，三种直接作用的抗病毒药物（DAAs）显著减少了新冠病毒肺炎的住院率和死亡率。然而，这些药物并不能完全预防重症疾病，并且与病情反弹和病毒脱落的病例有关。联合用药方案可以增强抗病毒效力，减少耐药变体的出现，并降低联合用药中每种成分的剂量。同时针对病毒进入和病毒复制为发现协同药物组合提供了机会。虽然联合抗病毒药物治疗是慢性RNA病毒感染的标准治疗方法，但尚无针对新冠病毒的联合抗病毒疗法获得批准。在此，我们证明将靶向TMPRSS2从而针对新冠病毒进入的宿主靶向抗病毒药物（HTAs）与靶向新冠病毒复制的直接作用抗病毒药物莫努匹韦联合使用，可协同抑制Calu - 3肺上皮细胞中的新冠病毒感染。当口服药物莫努匹韦与三种TMPRSS2（HTA）口服或吸入性抑制剂（卡莫司他、阿沃司他或萘莫司他）联合使用时，观察到了很强的协同作用。卡莫司他与莫努匹韦的组合对关注的贝塔和德尔塔变异株也有效。嘧啶生物合成抑制剂布雷喹纳与莫努匹韦联合使用也具有很强的协同抑制作用。这些HTA + DAA组合与莫努匹韦加奈玛特韦（帕克洛维德中的蛋白酶抑制剂）的协同全DAA组合具有相似的效力。药效学建模可以在合理的治疗范围内对每种药物在所有可能浓度下的抗病毒效力进行估计，表明可能具有体内疗效。卡莫司他、布雷喹纳和莫努匹韦的三联组合进一步提高了抗病毒效力。这些发现支持开发HTA + DAA组合用于大流行应对和防范。
重要性：想象一下未来的病毒大流行，如果检测出新病毒呈阳性，可以在家中快速服用一些药物持续几天，这样就不会病得太重。到目前为止，只有单一药物被批准用于门诊治疗新冠病毒，而且我们了解到这些药物有一些局限性，可能会产生耐药性。在此，我们表明两种口服药物的组合在阻断新冠病毒方面比单一药物更好，并且我们使用数学模型表明这些药物组合可能对人有效。我们还表明三种口服药物的组合在根除病毒方面效果更好。因此，我们的研究结果对开发在冠状病毒或其他新出现的病毒病原体感染的最初迹象时在家中使用的口服药物组合是个好兆头。
Three directly acting antivirals (DAAs) demonstrated substantial reduction in COVID-19 hospitalizations and deaths in clinical trials. However, these agents did not completely prevent severe illness and are associated with cases of rebound illness and viral shedding. Combination regimens can enhance antiviral potency, reduce the emergence of drug-resistant variants, and lower the dose of each component in the combination. Concurrently targeting virus entry and virus replication offers opportunities to discover synergistic drug combinations. While combination antiviral drug treatments are standard for chronic RNA virus infections, no antiviral combination therapy has been approved for SARS-CoV-2. Here, we demonstrate that combining host-targeting antivirals (HTAs) that target TMPRSS2 and hence SARS-CoV-2 entry, with the DAA molnupiravir, which targets SARS-CoV-2 replication, synergistically suppresses SARS-CoV-2 infection in Calu-3 lung epithelial cells. Strong synergy was observed when molnupiravir, an oral drug, was combined with three TMPRSS2 (HTA) oral or inhaled inhibitors: camostat, avoralstat, or nafamostat. The combination of camostat plus molnupiravir was also effective against the beta and delta variants of concern. The pyrimidine biosynthesis inhibitor brequinar combined with molnupiravir also conferred robust synergistic inhibition. These HTA+DAA combinations had similar potency to the synergistic all-DAA combination of molnupiravir plus nirmatrelvir, the protease inhibitor found in paxlovid. Pharmacodynamic modeling allowed estimates of antiviral potency at all possible concentrations of each agent within plausible therapeutic ranges, suggesting possible in vivo efficacy. The triple combination of camostat, brequinar, and molnupiravir further increased antiviral potency. These findings support the development of HTA+DAA combinations for pandemic response and preparedness. IMPORTANCE Imagine a future viral pandemic where if you test positive for the new virus, you can quickly take some medicines at home for a few days so that you do not get too sick. To date, only single drugs have been approved for outpatient use against SARS-CoV-2, and we are learning that these have some limitations and may succumb to drug resistance. Here, we show that combinations of two oral drugs are better than the single ones in blocking SARS-CoV-2, and we use mathematical modeling to show that these drug combinations are likely to work in people. We also show that a combination of three oral drugs works even better at eradicating the virus. Our findings therefore bode well for the development of oral drug cocktails for at home use at the first sign of an infection by a coronavirus or other emerging viral pathogens.
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影响因子：
5.8
作者：
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通讯作者：
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影响因子：
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作者：
Hoffmann M;Krüger N;Schulz S;Cossmann A;Rocha C;Kempf A;Nehlmeier I;Graichen L;Moldenhauer AS;Winkler MS;Lier M;Dopfer-Jablonka A;Jäck HM;Behrens GMN;Pöhlmann S
通讯作者：
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影响因子：
5.9
作者：
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通讯作者：
Fordyce, Marshall
DOI：
10.1056/nejmoa2116846
发表时间：
2022-01-27
期刊：
The New England journal of medicine
影响因子：
--
作者：
Gottlieb RL;Vaca CE;Paredes R;Mera J;Webb BJ;Perez G;Oguchi G;Ryan P;Nielsen BU;Brown M;Hidalgo A;Sachdeva Y;Mittal S;Osiyemi O;Skarbinski J;Juneja K;Hyland RH;Osinusi A;Chen S;Camus G;Abdelghany M;Davies S;Behenna-Renton N;Duff F;Marty FM;Katz MJ;Ginde AA;Brown SM;Schiffer JT;Hill JA;GS-US-540-9012 (PINETREE) Investigators
通讯作者：
GS-US-540-9012 (PINETREE) Investigators
影响因子：
4.6
作者：
Bai X;Buckle AM;Vladar EK;Janoff EN;Khare R;Ordway D;Beckham D;Fornis LB;Majluf-Cruz A;Fugit RV;Freed BM;Kim S;Sandhaus RA;Chan ED
通讯作者：
Chan ED