新型冠状病毒肺炎与血管紧张素转化酶2的研究现状

自2019年底起，新型冠状病毒肺炎（Coronavirus disease 2019，COVID-19）病例席卷全球。该病毒为β属冠状病毒，基因特征与严重急性呼吸综合征冠状病毒（Severe Acute Respiratory Syndrome Coronavirus，SARS-CoV）有较高相似性，被命名为2019新型冠状病毒（2019 Novel Coronavirus，2019-nCoV）或严重急性呼吸综合征冠状病毒-2（SARS-CoV-2），主要通过棘突蛋白介导与宿主血管紧张素转化酶2（angiotensin-converting enzyme 2，ACE2）受体结合侵犯人体。ACE2与COVID-19感染密切相关，既是SARS-CoV-2感染人体的关键靶点，ACE2表达多寡也是影响COVID-19患者疾病严重程度和死亡率的重要因素。因此靶向ACE2和肾素-血管紧张素系统（renin-angiotensin system，RAS）的诸多上市药物和在研药物，如血管紧张素转化酶抑制剂（angiotensin-converting enzyme inhibitor，ACEI）、血管紧张素受体拮抗剂（angiotensin receptor blocker，ARB）、重组人ACE2、Ⅱ型跨膜丝氨酸蛋白酶（type II transmembrane serine proteases，TMSPSS2）抑制剂、特异性中和抗体等都有可能成为治疗COVID-19的可行策略。此外，依据现有证据并不建议合并高血压的轻症COVID-19确诊病例或疑似病例轻易停用ACEI/ARB，以免造成血压波动。     

Amantadine disrupts lysosomal gene expression: A hypothesis for COVID19 treatment

SARS-coronavirus 2 is the causal agent of the COVID-19 outbreak. SARS-Cov-2 entry into a cell is dependent upon binding of the viral spike (S) protein to cellular receptor and on cleavage of the spike protein by the host cell proteases such as Cathepsin L and Cathepsin B. CTSL/B are crucial elements of lysosomal pathway and both enzymes are almost exclusively located in the lysosomes. CTSL disruption offers potential for CoVID-19 therapies. The mechanisms of disruption include: decreasing expression of CTSL, direct inhibition of CTSL activity and affecting the conditions of CTSL environment (increase pH in the lysosomes).We have conducted a high throughput drug screen gene expression analysis to identify compounds that would downregulate the expression of CTSL/CTSB. One of the top significant results shown to downregulate the expression of the CTSL gene is amantadine (10uM). Amantadine was approved by the US Food and Drug Administration in 1968 as a prophylactic agent for influenza and later for Parkinson's disease. It is available as a generic drug.Amantadine in addition to downregulating CTSL appears to further disrupt lysosomal pathway, hence, interfering with the capacity of the virus to replicate. It acts as a lysosomotropic agent altering the CTSL functional environment.  We hypothesize that amantadine could decrease the viral load in SARS-CoV-2 positive patients and as such it may serve as a potent therapeutic decreasing the replication and infectivity of the virus likely leading to better clinical outcomes. Clinical studies will be needed to examine the therapeutic utility of amantadine in COVID-19 infection.     

Importance of early precautionary actions in avoiding the spread of COVID-19: Saudi Arabia as an Example

Late in 2019, several cases of infection with a new strain of coronavirus were reported in China. This new strain was later officially named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the World Health Organization (WHO). This new virus (SARS-CoV2-) mainly affects the respiratory system and causes coronavirus disease 2019 (COVID-19). The first case of COVID-19 was reported to the WHO on December 31st, 2019, and the virus has spread dramatically in many countries worldwide. On March 11th, 2020, the WHO declared that COVID-19 had affected most of the world, and many deaths were linked to COVID-19. Unfortunately, there is no available treatment for COVID-19, and there is no available vaccine against SARS-CoV-2. Thus, preventive methods are the only way to limit the spread of the virus. Preventive actions have been taken by many countries, such as travel bans, closing borders and working from home. Saudi Arabia was one of the countries that took very early precautionary actions in the belief that these actions are the best way to fight the virus. Therefore, we present the actions that were taken by the Kingdom of Saudi Arabia to fight the new viral pandemic.     

Repurposing carrimycin as an antiviral agent against human coronaviruses,including the currently pandemic SARS-CoV-2

COVID-19 pandemic caused by SARS-CoV-2 infection severely threatens global health and economic development. No effective antiviral drug is currently available to treat COVID-19 and any other human coronavirus infections. We report herein that a macrolide antibiotic, carrimycin, potently inhibited the cytopathic effects (CPE) and reduced the levels of viral protein and RNA in multiple cell types infected by human coronavirus 229E, OC43, and SARS-CoV-2. Time-of-addition and pseudotype virus infection studies indicated that carrimycin inhibited one or multiple post-entry replication events of human coronavirus infection. In support of this notion, metabolic labelling studies showed that carrimycin significantly inhibited the synthesis of viral RNA. Our studies thus strongly suggest that carrimycin is an antiviral agent against a broad-spectrum of human coronaviruses and its therapeutic efficacy to COVID-19 is currently under clinical investigation.     

既往病毒性呼吸道传染疾病研究对抗COVID-19药物研发的启示

新型冠状病毒肺炎(COVID-19)疫情严重威胁人类的健康,并对世界经济造成了巨大损失。COVID-19是急性爆发性疾病,目前尚无靶向治疗特效药或疫苗上市,主要是对症支持治疗。由于时间紧迫,市场急需,这给医药领域的新药研发带来了巨大挑战。针对2019新型冠状病毒(SARS-CoV-2),充分借鉴既往的病毒(如流感病毒、SARS病毒、MERS病毒、埃博拉病毒等)引起的病毒性呼吸道传染疾病的防治理论和经验,快速形成有效的药物研发方案,是医药工业界应对新突发传染病的重要使命和有力抓手。本文综述了SARS-Co V-2与其他既往流行性病毒引起的急性呼吸道传染性疾病的发现、疫情蔓延和防治,剖析了病毒感染的发病机制,总结了既往病毒感染及防治药物的研究进展,以期为COVID-19的药物研发提供思路和启发。     

法匹拉韦治疗新冠肺炎临床研究进展

新型冠状病毒肺炎(COVID-19)疫情在全球大流行,临床上迫切需要特异性抗病毒治疗药物.对已批准上市或正在临床开发的药物开展重定位研究是针对突发疫情快速寻找潜在治疗药物最为快速和高效的策略.法匹拉韦是一种广谱抗RNA病毒药物,在日本和中国已批准上市用于治疗流感,其作为抗新型冠状病毒感染的潜在药物,全球多个国家正在开展...     

Antiviral Efficacy of Pralatrexate against SARS-CoV-2

Novel coronavirus (SARS-CoV-2) has caused more than 100 million confirmed cases of human infectious disease (COVID-19) since December 2019 to paralyze our global community. However, only limited access has been allowed to COVID-19 vaccines and antiviral treatment options. Here, we report the efficacy of the anticancer drug pralatrexate against SARS-CoV-2. In Vero and human lung epithelial Calu-3 cells, pralatrexate reduced viral RNA copies of SARS-CoV-2 without detectable cytotoxicity, and viral replication was successfully inhibited in a dose-dependent manner. In a time-to-addition assay, pralatrexate treatment at almost half a day after infection also exhibited inhibitory effects on the replication of SARS-CoV-2 in Calu-3 cells. Taken together, these results suggest the potential of pralatrexate as a drug repurposing COVID-19 remedy.     

儿童新型冠状病毒肺炎药物治疗研究进展

新型冠状病毒(severe acute respiratory syndrome corona virus,SARS-CoV)-2感染在全球暴发,目前尚无明确有效的抗病毒药物治疗SARS-CoV-2感染.结合以往临床一线治疗新型冠状病毒肺炎(corona virus disease 2019,COVID-19)的经验,...     

Telmisartan as tentative angiotensin receptor blocker therapeutic for COVID-19

In late 2019, a new coronavirus emerged in Wuhan Province, China, causing lung complications similar to those produced by the SARS coronavirus in the 2002–2003 epidemic. This new disease was named COVID-19 and the causative virus SARS-CoV-2. The SARS-CoV-2 virus enters the airway and binds, by means of the S protein on its surface to the membrane protein ACE2 in type 2 alveolar cells. The S protein-ACE2 complex is internalized by endocytosis leading to a partial decrease or total loss of the enzymatic function ACE2 in the alveolar cells and in turn increasing the tissue concentration of pro-inflammatory angiotensin II by decreasing its degradation and reducing the concentration of its physiological antagonist angiotensin 1–7. High levels of angiotensin II on the lung interstitium can promote apoptosis initiating an inflammatory process with release of proinflammatory cytokines, establishing a self-powered cascade, leading eventually to ARDS. Recently, Gurwitz proposed the tentative use of agents such as losartan and telmisartan as alternative options for treating COVID-19 patients prior to development of ARDS. In this commentary article, the authors make the case for the election of telmisartan as such alternative on the basis of its pharmacokinetic and pharmacodynamic properties and present an open-label randomized phase II clinical trial for the evaluation of telmisartan in COVID-19 patients ( NCT04355936 ).     

LPD-12: a promising lipopeptide to control COVID-19

Introduction: The recent pandemic outbreak of SARS-CoV-2 has been associated with a lethal atypical pneumonia, making COVID-19 an urgent public health issue with an increasing rate of mortality and morbidity. There are currently no vaccines or therapeutics available for COVID-19, which is causing an urgent search for a new drug to combat the COVID-19 pandemic. The lipid membrane alternation efficiency of small antimicrobial lipopeptides enables them to block viral membrane fusion to the host cell. Lipopeptides could serve as potential antiviral agents, by interacting or competing with viral fusion proteins.Methods: This study screened seven different lipopeptides (tsushimycin, daptomycin, surfactin, bacillomycin, iturin, srfTE, and LPD-12) and docked them individually against the spike (S)-glycoprotein of SARS-CoV-2.Results: Based on the maximum docked score and minimum atomic contact energy, LPD-12 (–1137.38 kcal) was the appropriate molecule for proper binding with the S-glycoprotein of SARS-CoV-2 and thus significantly interrupted its affinity of binding with angiotensin-converting enzyme-2 (ACE2), which is the only receptor molecule found to be facilitating disease development. The results confirmed a strong binding affinity of LPD-12 with ACE2, with a binding free energy of –1621.62 kcal, which could also reciprocally prevent the binding of S-protein.Conclustion: It can be concluded that LPD-12 may act as a potential therapeutic drug, by reducing the entry of SARS-CoV-2 to the human cells via the ACE2 receptor and related infections.     

Drugs Used in the Treatment of Multiple Sclerosis During COVID-19 Pandemic: A Critical Viewpoint

Since COVID-19 has emerged as a word public health problem, attention has been focused on how immune-suppressive drugs used for the treatment of autoimmune disorders influence the risk for SARS-CoV-2 infection and the development of acute respiratory distress syndrome (ARDS). Here, we discuss the disease-modifying agents approved for the treatment of multiple sclerosis (MS) within this context. Interferon (IFN)-β1a and -1b, which display antiviral activity, could be protective in the early stage of COVID-19 infection, although SARS-CoV-2 may have developed resistance to IFNs. However, in the hyperinflammation stage, IFNs may become detrimental by facilitating macrophage invasion in the lung and other organs. Glatiramer acetate and its analogues should not interfere with the development of COVID-19 and may be considered safe. Teriflunomide, a first-line oral drug used in the treatment of relapsing-remitting MS (RRMS), may display antiviral activity by depleting cellular nucleotides necessary for viral replication. The other first-line drug, dimethyl fumarate, may afford protection against SARS-CoV-2 by activating the Nrf-2 pathway and reinforcing the cellular defenses against oxidative stress. Concern has been raised regarding the use of second-line treatments for MS during the COVID-19 pandemic. However, this concern is not always justified. For example, fingolimod might be highly beneficial during the hyperinflammatory stage of COVID-19 for a number of mechanisms, including the reinforcement of the endothelial barrier. Caution is suggested for the use of natalizumab, cladribine, alemtuzumab, and ocrelizumab, although MS disease recurrence after discontinuation of these drugs may overcome a potential risk for COVID-19 infection.     

Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics

At the time of writing this commentary (February 2020), the coronavirus COVID-19 epidemic has already resulted in more fatalities compared with the SARS and MERS coronavirus epidemics combined. Therapeutics that may assist to contain its rapid spread and reduce its high mortality rates are urgently needed. Developing vaccines against the SARS-CoV-2 virus may take many months. Moreover, vaccines based on viral-encoded peptides may not be effective against future coronavirus epidemics, as virus mutations could make them futile. Indeed, new Influenza virus strains emerge every year, requiring new immunizations. A tentative suggestion based on existing therapeutics, which would likely be resistant to new coronavirus mutations, is to use available angiotensin receptor 1 (AT1R) blockers, such as losartan, as therapeutics for reducing the aggressiveness and mortality from SARS-CoV-2 virus infections. This idea is based on observations that the angiotensin-converting enzyme 2 (ACE2) very likely serves as the binding site for SARS-CoV-2, the strain implicated in the current COVID-19 epidemic, similarly to strain SARS-CoV implicated in the 2002–2003 SARS epidemic. This commentary elaborates on the idea of considering AT1R blockers as tentative treatment for SARS-CoV-2 infections, and proposes a research direction based on datamining of clinical patient records for assessing its feasibility.     

The fight against COVID-19: Striking a balance in the renin–angiotensin system

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells by interacting with membrane-bound angiotensin-converting enzyme 2 (ACE2), a vital element in the renin–angiotensin system (RAS), which regulates blood pressure, fluid balance, and cardiovascular functions. We herein evaluate existing evidence for the molecular alterations within the RAS pathway (e.g., ACE2 and angiotensin II) during SARS-CoV-2 infection and subsequent Coronavirus Disease 2019 (COVID-19). This includes reports regarding potential effect of RAS blockade (e.g., ACE inhibitors and angiotensin II receptor blockers) on ACE2 expression and clinical outcomes in patients with co-morbidities commonly treated with these agents. The collective evidence suggests a dual role for ACE2 in COVID-19, depending on the stage of infection and the coexisting diseases in individual patients. This information is further discussed with respect to potential therapeutic strategies targeting RAS for COVID-19 treatment.     

Managing COVID-19 in Renal Transplant Recipients: A Review of Recent Literature and Case Supporting Corticosteroid-sparing Immunosuppression

Novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome virus (SARS-CoV-2) has become a global health care crisis. The Centers for Disease Control and Prevention (CDC) lists immunocompromised patients, including those requiring immunosuppression following renal transplantation, as high risk for severe disease from SARS-CoV-2. Treatment for other viral infections in renal transplant recipients often includes a reduction in immunosuppression; however, no current guidelines are available recommending the optimal approach to managing immunosuppression in the patients who are infected with SARS-CoV-2. It is currently advised to avoid corticosteroids in the treatment of SARS-CoV-2 outside of critically ill patients. Recently published cases describing inpatient care of COVID-19 in renal transplant recipients differ widely in disease severity, time from transplantation, baseline immunosuppressive therapy, and the modifications made to immunosuppression during COVID-19 treatment. This review summarizes and compares inpatient immunosuppressant management strategies of recently published reports in the renal transplant population infected with SARS-CoV-2 and discusses the limitations of corticosteroids in managing immunosuppression in this patient population.     

Efficacy of repurposed antiviral drugs: Lessons from COVID-19

The clinical, social, and economic impacts of the coronavirus disease 2019 (COVID-19) pandemic, originated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have motivated a massive search and investment to find treatments for this new disease. Repurposing drugs has been an appealing strategy for the rapid translation of in vitro and ex vivo drug discovery to the clinic. Several repurposed drugs have been assessed clinically, but no effective repurposed antiviral has been identified so far. Of note, no effective treatments for COVID-19 or for any other viral disease have been found by repurposing drugs identified through hypothesis-free screens. Here, I discuss whether drug repurposing is the best strategy for developing effective therapies to eradicate COVID-19 and other viral human infections.     

Baricitinib: A Review of Pharmacology,Safety, and Emerging Clinical Experience in COVID-19

A hyperinflammatory response to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection, reminiscent of cytokine release syndrome, has been implicated in the pathophysiology of acute respiratory distress syndrome and organ damage in patients with coronavirus disease 2019 (COVID-19). Agents that inhibit components of the pro-inflammatory cascade have garnered interest as potential treatment options with hopes that dampening the proinflammatory process may improve clinical outcomes. Baricitinib is a reversible Janus-associated kinase (JAK)-inhibitor that interrupts the signaling of multiple cytokines implicated in COVID-19 immunopathology. It may also have antiviral effects by targeting host factors that viruses rely for cell entry and by suppressing type I interferon driven angiotensin-converting-enzyme-2 upregulation. However, baricitinib’s immunosuppressive effects may be detrimental during acute viral infections by delaying viral clearance and increasing vulnerability to secondary opportunistic infections. The lack of reliable biomarkers to monitor patients’ immune status as illness evolves complicates deployment of immunosuppressive drugs like baricitinib. Furthermore, baricitinib carries the risk of increased thromboembolic events, which is concerning given the proclivity towards a hypercoagulable state in patients with COVID-19. In this article, we review available data on baricitinib with an emphasis on immunosuppressive and antiviral pharmacology, pharmacokinetics, safety, and current progress in COVID-19 clinical trials.     

乌司他丁治疗新型冠状病毒肺炎可行性的研究进展

新型冠状病毒肺炎（COVID-19）仍在全球范围内传播,尚无特效药应用于临床。乌司他丁（ulinastatin）在抗炎方面发挥重要作用,临床上主要应用于急性胰腺炎、休克和弥散性血管内凝血等,其还具有抗氧化应激、抗凝、免疫调节作用,可能对于降低COVID-19的严重程度和死亡率有重要意义。主要结合乌司他丁的药理作用及其在治疗急性呼吸窘迫综合征、脓毒症肺损伤等COVID-19并发症中的临床应用,论述其应用于COVID-19的可行性,以期为该病的临床治疗及新药研发提供帮助。     

Two important controversial risk factors in SARS-CoV-2 infection: Obesity and smoking

The effects of obesity and smoking in the coronavirus disease 2019 (COVID-19) pandemic remain controversial. Angiotensin converting enzyme 2 (ACE2), a component of the renin-angiotensin system (RAS), is the human cell receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. ACE2 expression increases on lung alveolar epithelial cells and adipose tissue due to obesity, smoking and air pollution. A significant relationship exists between air pollution and SARS-CoV-2 infection, as more severe COVID-19 symptoms occur in smokers; comorbid conditions due to obesity or excess ectopic fat accumulation as underlying risk factors for severe COVID-19 strongly encourage the virus/ACE2 receptor-ligand interaction concept. Indeed, obesity, air pollution and smoking associated risk factors share underlying pathophysiologies that are related to the Renin-Angiotensin-System in SARS-CoV-2 infection. The aim of this review is to emphasize the mechanism of receptor-ligand interaction and its impact on the enhanced risk of death due to SARS-CoV-2 infection.