好消息！新冠疫情再見了！（永遠不再見了）
美國即將有「治療新冠病毒的口服液」。患有新冠狀病毒者在家口服該藥5天，體內徹底清除了新冠狀病毒，患者徹底康復。
該藥譯名為「莫那皮納偉」(Monapinavir)，由德國「瑞吉貝爾」(Rigibel) 和美國「默克」(Merck) 兩大藥廠聯合研製，已經在人體成功完成第一期和第二期臨床試驗，效果100%; 目前第三期臨床試驗接近收尾，效果非常好。 如果順利的話，在4~5個月內就可以面市。 該藥患者在家裡可以自己口服，5天痊癒，使用非常方便。 以後治新冠病毒就像現在治療普通感冒一樣。 新冠狀病毒就不可怕了。
該藥起初是針對流感病毒研製的。 它是化合物，原理是阻止病毒ia酶，也就是阻止病毒本身複製，從而根本上很快消滅病毒。 現在抗新冠病毒疫苗的原理是針對新冠病毒的凸緣，從而阻止新冠狀病毒和人體細胞結合。 這兩者的原理是不同的。
去年3~4月荷蘭和挪威養貂場發生貂患新冠狀病毒，導致貂百萬計的大規模死亡。 養貂場用「莫那皮納偉」喂貂，結果發現24小時後患病的貂內沒有新冠狀病毒了，養貂場很快終止了新冠狀病毒的傳播。 然後二大藥廠就在人體上進行第一期臨床試驗，成功後進行第二期，第三期臨床試驗，迄今為止即將正式上市了。
總之，這是科學界，特別是醫藥界的偉大成就。 也許它會繼安定，阿司匹林和青黴素，阿平為四大經典藥物。
*Molnupiravir: A New Hope For Prevention And Treatment Of Covid-19 And Other Dangerous Viruses*
https://www.forbes.com/sites/williamhaseltine/2021/03/16/molnupiravir-a-new-hope-for-prevention-and-treatment-of-covid-19-and-other-dangerous-viruses/
A new Covid-19 therapy has completed its phase two human trial and the results are promising. Molnupiravir, developed by Ridgeback Biotherapeutics LP and Merck & Co., reached its endpoint objective of reducing the length of Covid-19 infections, according to a Merck press release. This endpoint, among others, will be examined in greater depth upon the full data release from the trial.
一種新的 Covid-19 療法已經完成了第二階段的人體試驗，結果很有希望。根據默克公司的一份新聞稿，由 Ridgeback Biotherapeutics LP 和默克公司開發的 Molnupiravir 達到了縮短 Covid-19感染時間的終點目標。該終點等將在試驗的完整數據發布後進行更深入的研究。
Respiratory viruses like influenza, respiratory syncytial virus, and now Covid-19 are uniquely challenging to treat once symptoms arise. Because infections and symptoms for respiratory viruses are typically short-lived, the immune system quickly engages in viral replication suppression. Common form antivirals like Tamiflu and Xofluza for the flu, and now Remdesivir and monoclonal antibodies for Covid-19 must be administered within the first few days of infection to reduce symptom severity and infection duration.
一旦出現症狀，流感病毒、呼吸道合胞病毒和現在的 Covid-19 等呼吸道病毒都具有獨特的治療挑戰性。由於呼吸道病毒的感染和症狀通常是短暫的，因此免疫系統會迅速抑制病毒複製。常見形式的抗病毒藥物，如用於流感的達菲和 Xofluza，現在必須在感染的前幾天內使用 Remdesivir 和 Covid-19 的單克隆抗體，以減少症狀的嚴重程度和感染持續時間。
For respiratory antivirals, their ideal use is for those recently exposed to viruses from family members or workplaces. Following known exposure, Influenza A antiviral Xofluza reduced transmission by 80% in a close-quarter family context. For Covid-19, monoclonal antibodies have been shown to achieve similar close-quarter transmission effectiveness, but they have a catch. Unlike Xofluza, monoclonal antibodies require infusion outside the home. Xofluza and antivirals like it are pill-based, capable of home-use, and can be ingested quickly after exposure. This new drug, Molnupiravir, may be a Xofluza-like alternative for Covid-19, which could be a powerful addition to our armamentarium, in addition to vaccines, especially for variants that seem to escape vaccines.
對於呼吸道抗病毒藥物，它們的理想用途是那些最近接觸過來自家庭成員或工作場所的病毒的人。在已知暴露後，甲型流感抗病毒藥物 Xofluza 在近距離家庭環境中減少了 80% 的傳播。對於 Covid-19，單克隆抗體已被證明可實現類似的近距離傳播效果，但它們有一個問題。與 Xofluza 不同，單克隆抗體需要在家外輸注。 Xofluza 和類似的抗病毒藥物以藥丸為基礎，能夠在家使用，並且可以在暴露後迅速攝入。這種新藥 Molnupiravir 可能是 Covid-19 的類似 Xofluza 的替代品，除了疫苗之外，它可能是我們軍備的有力補充，尤其是對於似乎逃避疫苗的變種。
Molnupiravir was first developed as preventative medicine and treatment for SARS-CoV and MERS in the early 2000s. The drug has been previously shown to work against many viruses that employ an RNA-dependent RNA polymerase, which SARS-CoV-2 also has. The polymerase is the enzyme that copies the genetic material of the virus into new genetic material and produces the messenger RNAs that direct the production of all the viral proteins. Molnupiravir is a shape-shifter, called a tautomer. It assumes two forms, one which closely resembles uracil and the other cytosine.
Molnupiravir 最初是在 2000 年代初開發為 SARS-CoV 和 MERS 的預防藥物和治療方法。該藥物先前已被證明可以對抗許多采用 RNA 依賴性 RNA 聚合酶的病毒，SARS-CoV-2 也具有這種酶。聚合酶是一種酶，它將病毒的遺傳物質複製成新的遺傳物質，並產生指導所有病毒蛋白質產生的信使 RNA。 Molnupiravir 是一種變形劑，稱為互變異構體。它有兩種形式，一種與尿嘧啶非常相似，另一種與胞嘧啶非常相似。
Because it appears in these two different forms, once it is recopied, the replicating polymerase develops transition mutations, where a U nucleotide is converted to a C and a C to U. Copying RNA that contains Molnupiravir results in fatal flaws in the sequence, stopping replication, shortening infection, and limiting transmission. The figure below shows the replication process, and the red box indicates the polymerase mechanism with which Molnupiravir incorporates. The difference between the structure of an authentic nucleotide and Molnupiravir is apparently too subtle to trigger removal by the exonuclease repair function of the viral polymerase, a function that has bedeviled these of many other nucleoside inhibitors.
因為它以這兩種不同的形式出現，一旦它被重新復制，複製聚合酶就會發生過渡突變，其中 U 核苷酸轉換為 C，C 轉換為 U。複製包含莫努匹韋的 RNA 會導致序列中的致命缺陷，停止複製、縮短感染和限制傳播。下圖顯示了複製過程，紅框表示Molnupiravir摻入的聚合酶機制。真實核苷酸和莫努匹韋的結構之間的差異顯然太微妙，無法通過病毒聚合酶的外切核酸酶修復功能觸發去除，這一功能一直困擾著許多其他核苷抑製劑。
Early studies on Molnupiravir on SARS-CoV-2 in vitro indicated a logarithmic drop in virus production dependent on the dose of Molnupiravir introduced. This was possible because the RdRp of SARS-CoV-2 and SARS-CoV, which the drug was initially intended to treat, have 99.1% nucleotide similarity. Whole-genome deep-sequencing showed dose-dependent accumulation of random low-frequency mutations. Repeat exposure of virus populations to the drug was rapidly sterilizing, confirming that none of the random mutations mediate resistance to the drug. In the figures below, titer levels and genome production of SARS-CoV-2 decrease as the drug is introduced in higher volumes. At the time of the early study, mouse models and human testing were not yet available for Molnupiravir, but human trials began in June 2020.
Molnupiravir在體外對 SARS-CoV-2 的早期研究表明病毒產量的對數下降取決於引入的 Molnupiravir 劑量。這是可能的，因為 SARS-CoV-2 和該藥物最初打算治療的 SARS-CoV 的 RdRp 具有 99.1% 的核苷酸相似性。全基因組深度測序顯示隨機低頻突變的劑量依賴性積累。病毒群體反復接觸藥物會迅速消毒，證實沒有任何隨機突變介導對藥物的耐藥性。在下圖中，SARS-CoV-2 的滴度水平和基因組產量隨著藥物的大量引入而下降。在早期研究時，Molnupiravir 還沒有小鼠模型和人體測試，但人體試驗於 2020 年 6 月開始。
As detailed in a press release by Merck & Co, the preliminary results of these trials are promising. The trial was comprised of non-hospitalized adults who had symptoms of Covid-19 within seven days and confirmed SARS-CoV-2 infection.
The released details indicate that Molnupiravir in its full dosage prompts a reduction in days to negativity for the virus in nasopharyngeal swabs taken from participants with symptomatic SARS-CoV-2 infections. Five days after dose administration, 0% of those who received the dose were positive for the virus (0/47) compared with 24% of the placebo group (6/25). While details and study size is limited, a measurable drop in infection length is significant, as shorter infections may yield a smaller chance of transmission or severe symptoms.
The Merck press release follows a detailed study of this polymerase inhibitor in ferrets, given that ferrets and related members of the weasel genus can transmit viruses asymptomatically, resembling the human spread of viruses. Researchers found that this drug not only prevents close-quarter animal groupings from becoming as sick but the drug also reduces transmission of the virus. The figure below demonstrates the ferret study duration and test grouping. These results may very well be replicated in human trials when that data is released in the coming weeks.
正如默克公司在新聞稿中所詳述的那樣，這些試驗的初步結果很有希望。該試驗由在 7 天內出現 Covid-19 症狀並確認感染 SARS-CoV-2 的非住院成年人組成。 已發布的細節表明，全劑量的 Molnupiravir 促使從有症狀的 SARS-CoV-2 感染的參與者身上採集的鼻咽拭子中病毒呈陰性的天數減少。給藥五天后，0% 的接受該劑量的患者對病毒呈陽性 (0/47)，而安慰劑組為 24% (6/25)。雖然細節和研究規模有限，但感染時間的顯著下降是顯著的，因為感染時間越短，傳播或嚴重症狀的機會就越小。
鑑於雪貂和黃鼠狼屬的相關成員可以無症狀地傳播病毒，類似於病毒在人類中的傳播，默克公司的新聞稿遵循了對這種聚合酶抑製劑在雪貂中的詳細研究。研究人員發現，這種藥物不僅可以防止近距離動物群體變得如此病態，而且還可以減少病毒的傳播。下圖展示了雪貂研究的持續時間和測試分組。當這些數據在未來幾週內發佈時，這些結果很可能會在人體試驗中得到復制。
The positive results of Molnupiravir represent an emerging hope for more Covid-19 therapies to come. Its oral administration indicates a potential drug that could come before hospitalization and perhaps even prevent severe symptoms. Were a pill-based treatment for Covid-19 available, many lives would be easily saved and many hospital beds could be opened for those who need them.
In addition to its reduction of Covid-19 transmission, Molnupiravir is likely to be useful against influenza, ebola, and a large swath of other viruses as well. Its development appears to be a major advancement in virus control and should be active against Covid-19 variants and variants of other viruses. However, we caution Molnupiravir should be administered in conjunction with other therapies to avoid viruses rapidly developing resistance, which all these viruses are well-equipped to do.
Though, as these results are preliminary, we eagerly await the full release of the phase two data and the drug’s eventual full trial outcomes. This could be a real winner.
Molnupiravir 的積極結果代表了出現更多 Covid-19 療法的新希望。它的口服給藥表明一種潛在的藥物可以在住院前出現，甚至可能預防嚴重的症狀。如果有針對 Covid-19 的基於藥丸的治療方法，將可以輕鬆挽救許多生命，並且可以為需要的人開放許多病床。
除了減少 Covid-19 的傳播外，Molnupiravir 可能還有助於對抗流感、埃博拉病毒和大量其他病毒。它的發展似乎是病毒控制的重大進步，應該對 Covid-19 變種和其他病毒的變種有效。然而，我們提醒說，莫魯匹韋應與其他療法聯合使用，以避免病毒迅速產生耐藥性，而所有這些病毒都可以很好地做到這一點。
儘管如此，由於這些結果是初步的，我們熱切地等待第二階段數據的完整發佈以及該藥物最終的完整試驗結果。這可能是一個真正的贏家。
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