The SARS-CoV-2 pandemic and its unprecedented global societal and economic disruptive impact has marked the third zoonotic introduction of a highly pathogenic coronavirus into the human population. Although the previous coronavirus SARS-CoV and MERS-CoV epidemics raised awareness of the need for clinically available therapeutic or preventive interventions, to date, no treatments with proven efficacy are available. The development of effective intervention strategies relies on the knowledge of molecular and cellular mechanisms of coronavirus infections, which highlights the significance of studying virus-host interactions at the molecular level to identify targets for antiviral intervention and to elucidate critical viral and host determinants that are decisive for the development of severe disease. In this Review, we summarize the first discoveries that shape our current understanding of SARS-CoV-2 infection throughout the intracellular viral life cycle and relate that to our knowledge of coronavirus biology. The elucidation of similarities and differences between SARS-CoV-2 and other coronaviruses will support future preparedness and strategies to combat coronavirus infections.

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Coronavirus biology and replication: implications for SARS-CoV-2.

The infection of a novel coronavirus found in Wuhan of China (SARS-CoV-2) is rapidly spreading, and the incidence rate is increasing worldwide. Due to the lack of effective treatment options for SARS-CoV-2, various strategies are being tested in China, including drug repurposing. In this study, we used our pre-trained deep learning-based drug-target interaction model called Molecule Transformer-Drug Target Interaction (MT-DTI) to identify commercially available drugs that could act on viral proteins of SARS-CoV-2. The result showed that atazanavir, an antiretroviral medication used to treat and prevent the human immunodeficiency virus (HIV), is the best chemical compound, showing an inhibitory potency with Kd of 94.94 nM against the SARS-CoV-2 3C-like proteinase, followed by remdesivir (113.13 nM), efavirenz (199.17 nM), ritonavir (204.05 nM), and dolutegravir (336.91 nM). Interestingly, lopinavir, ritonavir, and darunavir are all designed to target viral proteinases. However, in our prediction, they may also bind to the replication complex components of SARS-CoV-2 with an inhibitory potency with Kd

Predicting commercially available antiviral drugs that may act on the novel coronavirus (SARS-CoV-2) through a drug-target interaction deep learning model

Candidate drugs against SARS-CoV-2 and COVID-19.

OBJECTIVE: To evaluate the effect of coronavirus disease 2019 (COVID-19) on maternal, perinatal and neonatal outcome by performing a systematic review of available published literature on pregnancies affected by COVID-19. METHODS: We performed a systematic review to evaluate the effect of COVID-19 on pregnancy, perinatal and neonatal outcome. We conducted a comprehensive literature search using PubMed, EMBASE, the Cochrane Library, China National Knowledge Infrastructure Database and Wan Fang Data up to and including 20 April 2020 (studies were identified through PubMed alert after that date). For the search strategy, combinations of the following keywords and medical subject heading (MeSH) terms were used: 'SARS-CoV-2', 'COVID-19', 'coronavirus disease 2019', 'pregnancy', 'gestation', 'maternal', 'mother', 'vertical transmission', 'maternal-fetal transmission', 'intrauterine transmission', 'neonate', 'infant' and 'delivery'. Eligibility criteria included laboratory-confirmed and/or clinically diagnosed COVID-19, patient being pregnant on admission and availability of clinical characteristics, including at least one maternal, perinatal or neonatal outcome. Exclusion criteria were non-peer-reviewed or unpublished reports, unspecified date and location of the study, suspicion of duplicate reporting and unreported maternal or perinatal outcomes. No language restrictions were applied. RESULTS: We identified a high number of relevant case reports and case series, but only 24 studies, including a total of 324 pregnant women with COVID-19, met the eligibility criteria and were included in the systematic review. These comprised nine case series (eight consecutive) and 15 case reports. A total of 20 pregnant patients with laboratory-confirmed COVID-19 were included in the case reports. In the combined data from the eight consecutive case series, including 211 (71.5%) cases of laboratory-confirmed and 84 (28.5%) of clinically diagnosed COVID-19, the maternal age ranged from 20 to 44 years and the gestational age on admission ranged from 5 to 41 weeks. The most common symptoms at presentation were fever, cough, dyspnea/shortness of breath, fatigue and myalgia. The rate of severe pneumonia reported amongst the case series ranged from 0% to 14%, with the majority of the cases requiring admission to the intensive care unit. Almost all cases from the case series had positive computed tomography chest findings. All six and 22 cases that had nucleic-acid testing in vaginal mucus and breast milk samples, respectively, were negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Only four cases of spontaneous miscarriage or termination were reported. In the consecutive case series, 219/295 women had delivered at the time of reporting and 78% of them had Cesarean section. The gestational age at delivery ranged from 28 to 41 weeks. Apgar scores at both 1 and 5 min ranged from 7 to 10. Only eight neonates had birth weight < 2500 g and nearly one-third of neonates were transferred to the neonatal intensive care unit. There was one case of neonatal asphyxia and death. In 155 neonates that had nucleic-acid testing in throat swab, all, except three cases, were negative for SARS-CoV-2. There were no cases of maternal death in the eight consecutive case series. Seven maternal deaths, four intrauterine fetal deaths (one with twin pregnancy) and two neonatal deaths (twin pregnancy) were reported in a non-consecutive case series of nine cases with severe COVID-19. In the case reports, two maternal deaths, one neonatal death and two cases of neonatal SARS-CoV-2 infection were reported. CONCLUSIONS: Despite the increasing number of published studies on COVID-19 in pregnancy, there are insufficient good-quality data to draw unbiased conclusions with regard to the severity of the disease or specific complications of COVID-19 in pregnant women, as well as vertical transmission, perinatal and neonatal complications. In order to answer specific questions in relation to the impact of COVID-19 on pregnant women and their fetuses, through meaningful good-quality research, we urge researchers and investigators to present complete outcome data and reference previously published cases in their publications, and to record such reporting when the data of a case are entered into one or several registries. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

https://obgyn.onlinelibrary.wiley.com/doi/pdf/10.1002/uog.22088

Effect of coronavirus disease 2019 (COVID-19) on maternal, perinatal and neonatal outcome: systematic review.

Maternal death due to COVID-19.

SUMMARY A new coronavirus (CoV) identified as COVID-19 virus is the etiological agent responsible for the 2019-2020 viral pneumonia outbreak that commenced in Wuhan1-4. Currently there is no targeted therapeutics and effective treatment options remain very limited. In order to rapidly discover lead compounds for clinical use, we initiated a program of combined structure-assisted drug design, virtual drug screening and high-throughput screening to identify new drug leads that target the COVID-19 virus main protease (Mpro). Mpro is a key CoV enzyme, which plays a pivotal role in mediating viral replication and transcription, making it an attractive drug target for this virus5,6. Here, we identified a mechanism-based inhibitor, N3, by computer-aided drug design and subsequently determined the crystal structure of COVID-19 virus Mpro in complex with this compound. Next, through a combination of structure-based virtual and high-throughput screening, we assayed over 10,000 compounds including approved drugs, drug candidates in clinical trials, and other pharmacologically active compounds as inhibitors of Mpro. Six of these inhibit Mpro with IC50 values ranging from 0.67 to 21.4 μM. Ebselen also exhibited strong antiviral activity in cell-based assays. Our results demonstrate the efficacy of this screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases where no specific drugs or vaccines are available.

https://www.biorxiv.org/content/biorxiv/early/2020/03/29/2020.02.26.964882.full.pdf

Structure of Mpro from COVID-19 virus and discovery of its inhibitors

Ilomastat, a broad-spectrum inhibitor of matrix metalloproteinases (MMPs), has drawn attentions for its function in alleviating radiation damage. However, the detailed mechanisms of Ilomastat’s protection from animal model remain not fully clear. In this study, the C57BL/6 mice were pre-administrated with Ilomastat or vihicle for 2 h, and then total body of mice were exposed to 6 Gy of γ-rays. The protective effect of Ilomastat on the hematopoietic system in the irradiated mice were investigated. We found that pretreatment with Ilomastat significantly reduced the level of TGF-β1 and TNF-α, and elevated the number of bone marrow (BM) mononuclear cells in the irradiated mice. Ilomastat pretreatment also increased the fraction of BM hematopoietic progenitor cells (HPCs) and hematopoietic stem cells (HSCs) at day 30 after irradiation, and protected the spleen of mouse from irradiation. These results suggest that Ilomastat promotes the recovery of hematopoietic injury in the irradiated mice, and thus contributes to the survival of mouse after irradiation.

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Ilomastat contributes to the survival of mouse after irradiation via promoting the recovery of hematopoietic system

Ilomastat, a broad-spectrum inhibitor of matrix metalloproteinases (MMPs), has drawn attentions for its function in alleviating radiation damage. However, the detailed mechanisms of Ilomastat's protection from animal model remain not fully clear. In this study, the C57BL/6 mice were pre-administrated with Ilomastat or vihicle for 2 h, and then total body of mice were exposed to 6 Gy of γ-rays. The protective effect of Ilomastat on the hematopoietic system in the irradiated mice were investigated. We found that pretreatment with Ilomastat significantly reduced the level of TGF-β1 and TNF-α, and elevated the number of bone marrow (BM) mononuclear cells in the irradiated mice. Ilomastat pretreatment also increased the fraction of BM hematopoietic progenitor cells (HPCs) and hematopoietic stem cells (HSCs) at day 30 after irradiation, and protected the spleen of mouse from irradiation. These results suggest that Ilomastat promotes the recovery of hematopoietic injury in the irradiated mice, and thus contributes to the survival of mouse after irradiation.

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Xingzhou Li

Papers

Structure of Mpro from COVID-19 virus and discovery of its inhibitors

Ilomastat contributes to the survival of mouse after irradiation via promoting the recovery of hematopoietic system

Ilomastat contributes to the survival of mouse after irradiation via promoting the recovery of hematopoietic system.