瑞德西韋

---

瑞德西韋(Remdesivir)是一種模擬核苷酸抑制劑，在體外對多種病毒具有有效的抗病毒活性，包括埃博拉病毒，馬爾堡病毒，HCoV-NL63，HCoV-OC43，HCoV-229E，小鼠肝炎病毒（MHV），SARS-CoV，MERS-CoV 以及相關的蝙蝠冠狀病毒，HKU5和PDCoV（豬三角洲冠狀病毒）。 Remdesivir還據報道對2019年新型冠狀病毒（稱為2019-nCoV，nCoV2019或COVID-19）具有潛在的抗病毒活性。

---

Remdesivir或GS-5734是一種三磷酸腺苷類似物，于2016年首次在文獻中描述為可能的埃博拉病毒治療方法.2017年，它還被證明了對冠狀病毒家族類病毒的活性有抑制作用。 SARS-CoV-2的潛在治療方法，冠狀病毒負責COVID-19。
Remdesivir, or GS-5734, is an adenosine triphosphate analog first described in the literature in 2016 as a potential treatment for Ebola.In 2017, its activity against the coronavirus family of viruses was also demonstrated.Remdesivir is also being researched as a potential treatment to SARS-CoV-2, the coronavirus responsible for COVID-19.

---

Remdesivir是一種核苷類似物，有望抑制RNA聚合酶的作用。通過摻入RNA不能添加額外的核苷酸，從而終止RNA轉錄。已證明RNA聚合酶突變的病毒對remdesivir產生部分抗性傳染性較小。
Remdesivir is a nucleoside analog that is expected to inhibit the action of RNA polymerase.By incorporating into RNA, additional nucleotides cannot be added, terminating RNA transcription.Viruses with mutations in RNA polymerase to develop partial resistance to remdesivir have been shown to be less infective.

---

瑞德西韋研究進展：

---

1.準備在埃博拉疫情中使用的實驗藥物
檢查海頓E.
國際衛生組織正在與剛果民主共和國討論如何以及是否采用除疫苗之外的其他療法。 國際衛生組織正在與剛果民主共和國討論如何以及是否采用除疫苗之外的其他療法。 剛果衛生部官員攜帶了第一批實驗性埃博拉疫苗。

---

2.發現用于治療埃博拉病毒的藥物
Bixler SL，Duplantier AJ，Bavari S.
審查目的：
埃博拉病毒（Filoviridae家族）的成員，是人類嚴重病毒性出血熱的病原體。在過去的40年中，該病毒與非洲幾次高死亡率暴發有關，最近在西非暴發導致11,000多人死亡。這篇綜述總結了埃博拉病毒病治療藥物的藥物發現和開發過程的現狀，重點是所使用的策略以及該過程各個階段面臨的挑戰。最近發現：盡管有大量的體外功效數據，動物模型中的臨床前數據以及人類臨床數據，但尚未批準任何療法可用于治療埃博拉病毒病。但是，一些有希望的候選人，例如ZMapp和GS-5734，已經進入正在進行的臨床試驗。

---

瑞德西韋（GS-5734）在體外有效抑制MERS冠狀病毒（MERS-CoV）復制，并在小鼠模型中顯示出對嚴重急性呼吸系統綜合癥（SARS）-CoV的功效。在這里，我們 在MERS-CoV感染的非人類靈長類動物模型恒河猴中測試了預防和治療性瑞姆昔韋治療的功效。植入前24小時開始的預防性remdesivir治療完全預防了MERS-CoV引起的臨床 疾病后，嚴重抑制了呼吸系統中MERS-CoV的復制，并防止了肺部病變的形成。注入后12小時開始的雷姆昔韋韋治療還提供了明顯的臨床癥狀，包括臨床體征減少，肺部 此處提供的數據支持在MERS臨床試驗中對雷姆昔韋韋的治療效果進行測試。還可以考慮將其用于更廣泛的冠狀病毒，包括 當前新興的新型冠狀病毒2019-nCoV。

---

BIOFOUNT公司目前衍生的瑞德西韋產品有：瑞德西韋一磷酸、瑞德西韋二磷酸、瑞德西韋三磷酸、瑞德西韋異構體等形式產品。

---

瑞德西韋的要用半衰期：在非人類靈長類動物中靜脈內劑量為10mg / kg時，血漿半衰期為0.39h。在非人類靈長類動物中，核苷三磷酸代謝物的半衰期為14h。

---

1. Warren TK, Jordan R, Lo MK, Ray AS, Mackman RL, Soloveva V, Siegel D, Perron M, Bannister R, Hui HC, Larson N, Strickley R, Wells J, Stuthman KS, Van Tongeren SA, Garza NL, Donnelly G, Shurtleff AC, Retterer CJ, Gharaibeh D, Zamani R, Kenny T, Eaton BP, Grimes E, Welch LS, Gomba L, Wilhelmsen CL, Nichols DK, Nuss JE, Nagle ER, Kugelman JR, Palacios G, Doerffler E, Neville S, Carra E, Clarke MO, Zhang L, Lew W, Ross B, Wang Q, Chun K, Wolfe L, Babusis D, Park Y, Stray KM, Trancheva I, Feng JY, Barauskas O, Xu Y, Wong P, Braun MR, Flint M, McMullan LK, Chen SS, Fearns R, Swaminathan S, Mayers DL, Spiropoulou CF, Lee WA, Nichol ST, Cihlar T, Bavari S: Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature. 2016 Mar 17;531(7594):381-5. doi: 10.1038/nature17180. Epub 2016 Mar 

2. ---

   Sheahan TP, Sims AC, Graham RL, Menachery VD, Gralinski LE, Case JB, Leist SR, Pyrc K, Feng JY, Trantcheva I, Bannister R, Park Y, Babusis D, Clarke MO, Mackman RL, Spahn JE, Palmiotti CA, Siegel D, Ray AS, Cihlar T, Jordan R, Denison MR, Baric RS: Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med. 2017 Jun 28;9(396). pii: 9/396/eaal3653. doi: 10.1126/scitranslmed.aal3653. 

3. ---

   Agostini ML, Andres EL, Sims AC, Graham RL, Sheahan TP, Lu X, Smith EC, Case JB, Feng JY, Jordan R, Ray AS, Cihlar T, Siegel D, Mackman RL, Clarke MO, Baric RS, Denison MR: Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease. mBio. 2018 Mar 6;9(2). pii: mBio.00221-18. doi: 10.1128/mBio.00221-18.

4. ---

   de Wit E, Feldmann F, Cronin J, Jordan R, Okumura A, Thomas T, Scott D, Cihlar T, Feldmann H: Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc Natl Acad Sci U S A. 2020 Feb 13. pii: 1922083117. doi: 10.1073/pnas.1922083117. 

5. ---

   Vander T, Medvedovsky M, Herishanu Y: Encephalopathy induced by oral acyclovir in a patient with normal renal function. J Infect. 2003 May;46(4):286. doi: 10.1053/jinf.2002.1119. 

6. ---

   Ko WC, Rolain JM, Lee NY, Chen PL, Huang CT, Lee PI, Hsueh PR: Arguments in favor of remdesivir for treating SARS-CoV-2 infections. Int J Antimicrob Agents. 2020 Mar 5:105933. doi: 10.1016/j.ijantimicag.2020.105933. 

7. ---

   Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A, Feldt T, Green G, Green ML, Lescure FX, Nicastri E, Oda R, Yo K, Quiros-Roldan E, Studemeister A, Redinski J, Ahmed S, Bernett J, Chelliah D, Chen D, Chihara S, Cohen SH, Cunningham J, D'Arminio Monforte A, Ismail S, Kato H, Lapadula G, L'Her E, Maeno T, Majumder S, Massari M, Mora-Rillo M, Mutoh Y, Nguyen D, Verweij E, Zoufaly A, Osinusi AO, DeZure A, Zhao Y, Zhong L, Chokkalingam A, Elboudwarej E, Telep L, Timbs L, Henne I, Sellers S, Cao H, Tan SK, Winterbourne L, Desai P, Mera R, Gaggar A, Myers RP, Brainard DM, Childs R, Flanigan T: Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med. 2020 Apr 10. doi: 10.1056/NEJMoa2007016. 

8. ---

   Ledford H: Hopes rise on coronavirus drug remdesivir. Nature. 2020 Apr 29. pii: 10.1038/d41586-020-01295-8. doi: 10.1038/d41586-020-01295-8. 

---

※ Experimental drugs poised for use in Ebola outbreak
Check Hayden E.
International health organizations are in discussions with the Democratic Republic of Congo about how and whether to deploy treatments in addition to a vaccine. International health organizations are in discussions with the Democratic Republic of Congo about how and whether to deploy treatments in addition to a vaccine. Congolese Health Ministry officials carry the first batch of experimental Ebola vaccines.

---

※ Initiation, extension, and termination of RNA synthesis by a paramyxovirus polymerase
Jordan PC, Liu C, Raynaud P, Lo MK, Spiropoulou CF, Symons JA, Beigelman L, Deval J.
Paramyxoviruses represent a family of RNA viruses causing significant human diseases. These include measles virus, the most infectious virus ever reported, in addition to parainfluenza virus, and other emerging viruses. Paramyxoviruses likely share common replication machinery but their mechanisms of RNA biosynthesis activities and details of their complex polymerase structures are unknown. Mechanistic and functional details of a paramyxovirus polymerase would have sweeping implications for understanding RNA virus replication and for the development of new antiviral medicines. To study paramyxovirus polymerase structure and function, we expressed an active recombinant Nipah virus (NiV) polymerase complex assembled from the multifunctional NiV L protein bound to its phosphoprotein cofactor. NiV is an emerging highly pathogenic virus that causes severe encephalitis and has been declared a global public health concern due to its high mortality rate. Using negative-stain electron microscopy, we demonstrated NiV polymerase forms ring-like particles resembling related RNA polymerases. We identified conserved sequence elements driving recognition of the 3'-terminal genomic promoter by NiV polymerase, and leading to initiation of RNA synthesis, primer extension, and transition to elongation mode. Polyadenylation resulting from NiV polymerase stuttering provides a mechanistic basis for transcription termination. It also suggests a divergent adaptation in promoter recognition between pneumo- and paramyxoviruses. The lack of available antiviral therapy for NiV prompted us to identify the triphosphate forms of R1479 and GS-5734, two clinically relevant nucleotide analogs, as substrates and inhibitors of NiV polymerase activity by delayed chain termination. Overall, these findings provide low-resolution structural details and the mechanism of an RNA polymerase from a previously uncharacterized virus family. This work illustrates important functional differences yet remarkable similarities between the polymerases of nonsegmented negative-strand RNA viruses.

---

※ Discovering Drugs for the Treatment of Ebola Virus
Bixler SL, Duplantier AJ, Bavari S.
PURPOSE OF REVIEW:
Ebola virus, a member of the Filoviridae family, is a causative agent of severe viral hemorrhagic fever in humans. Over the past 40 years, the virus has been linked to several high mortality outbreaks in Africa with the recent West African outbreak resulting in over 11,000 deaths. This review provides a summary of the status of the drug discovery and development process for therapeutics for Ebola virus disease, with a focus on the strategies being used and the challenges facing each stage of the process.
RECENT FINDINGS:
Despite the wealth of in vitro efficacy data, preclinical data in animal models, and human clinical data, no therapeutics have been approved for the treatment of Ebola virus disease. However, several promising candidates, such as ZMapp and GS-5734, have advanced into ongoing clinical trials.
SUMMARY:
The gravity of the 2014-2016 outbreak spurred a heightened effort to identify and develop new treatments for Ebola virus disease, including small molecules, immunotherapeutics, host factors, and clinical disease management options.
DISCLAIMER:
Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endoresed by the U.S. Army.

---

※ Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses
Sheahan TP, Sims AC, Graham RL, Menachery VD, Gralinski LE, Case JB, Leist SR, Pyrc K, Feng JY, Trantcheva I, Bannister R, Park Y, Babusis D, Clarke MO, Mackman RL, Spahn JE, Palmiotti CA, Siegel D, Ray AS, Cihlar T, Jordan R, Denison MR, Baric RS.
Emerging viral infections are difficult to control because heterogeneous members periodically cycle in and out of humans and zoonotic hosts, complicating the development of specific antiviral therapies and vaccines. Coronaviruses (CoVs) have a proclivity to spread rapidly into new host species causing severe disease. Severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV) successively emerged, causing severe epidemic respiratory disease in immunologically naïve human populations throughout the globe. Broad-spectrum therapies capable of inhibiting CoV infections would address an immediate unmet medical need and could be invaluable in the treatment of emerging and endemic CoV infections. We show that a nucleotide prodrug, GS-5734, currently in clinical development for treatment of Ebola virus disease, can inhibit SARS-CoV and MERS-CoV replication in multiple in vitro systems, including primary human airway epithelial cell cultures with submicromolar IC50 values. GS-5734 was also effective against bat CoVs, prepandemic bat CoVs, and circulating contemporary human CoV in primary human lung cells, thus demonstrating broad-spectrum anti-CoV activity. In a mouse model of SARS-CoV pathogenesis, prophylactic and early therapeutic administration of GS-5734 significantly reduced lung viral load and improved clinical signs of disease as well as respiratory function. These data provide substantive evidence that GS-5734 may prove effective against endemic MERS-CoV in the Middle East, circulating human CoV, and, possibly most importantly, emerging CoV of the future.