Summary Zika virus (ZIKV) infects fetal and adult human brain, and is associated with serious neurological complications. To date, no therapeutic treatment is available to treat ZIKV infected patients. We performed a high content chemical screen using human embryonic stem cell derived cortical neuron progenitor cells (hNPCs) and found that hippeastrine hydrobromide (HH) and amodiaquine dihydrochloride dihydrate (AQ), can inhibit ZIKV infection in hNPCs. Further validation showed that HH also rescues ZIKV-induced growth and differentiation defects in hNPCs and human fetal-like forebrain organoids. Finally, HH and AQ inhibit ZIKV infection in adult mouse brain in vivo. Strikingly, HH suppresses viral propagation when administered to adult mice with active ZIKV infection, highlighting its therapeutic potential. Our approach highlights the power of stem cell-based screens and validation in human forebrain organoids and mouse models in identifying drug candidates for treating ZIKV infection and related neurological complications in fetal and adult patients.
BackgroundThis study was designed to mainly evaluate the activity and safety of olanzapine compared with 5-hydroxytryptamine3(5-HT3) receptor antagonists for prevention of chemotherapy-induced nausea and vomiting(CINV) in patients receiving highly or moderately emetogenic chemotherapy (HEC or MEC). The second goal was to evaluate the impact of olanzapine on quality of life (QoL) of cancer patients during the period of chemotherapy.Methods229 patients receiving highly or moderately emetogenic chemotherapy were randomly assigned to the test group [olanzapine(O) 10 mg p.o. plus azasetron (A) 10 mg i.v. and dexamethasone (D) 10 mg i.v. on day 1; O 10 mg once a day on days 2-5] or the control group (A 10 mg i.v. and D 10 mg i.v. on day 1; D 10 mg i.v. once a day on days 2-5). All the patients filled the observation table of CINV once a day on days 1-5, patients were instructed to fill the EORTC QLQ-C30 QoL observation table on day 0 and day 6. The primary endpoint was the complete response (CR) (without nausea and vomiting, no rescue therapy) for the acute period (24 h postchemotherapy), delayed period (days 2-5 poschemotherapy), the whole period (days 1-5 postchemotherapy). The second endpoint was QoL during chemotherapy administration, drug safety and toxicity.Results229 patients were evaluable for efficacy. Compared with control group, complete response for acute nausea and vomiting in test group had no difference (p > 0.05), complete response for delayed nausea and vomiting in patients with highly emetogenic chemotherapy respectively improved 39.21% (69.64% versus 30.43%, p < 0.05), 22.05% (78.57% versus 56.52%, p < 0.05), complete response for delayed nausea and vomiting in patients with moderately emetogenic chemotherapy respectively improved 25.01% (83.07% versus 58.06%, p < 0.05), 13.43% (89.23% versus 75.80%, p < 0.05), complete response for the whole period of nausea and vomiting in patients with highly emetogenic chemotherapy respectively improved 41.38% (69.64% versus 28.26%, p < 0.05), 22.05% (78.57% versus 56.52%, p < 0.05), complete response for the whole period of nausea and vomiting in patients with moderately emetogenic chemotherapy respectively improved 26.62% (83.07% versus 56.45%, p < 0.05), 13.43% (89.23% versus 75.80%, p < 0.05). 214 of 299 patients were evaluable for QoL. Comparing test group with control group in QoL evolution, significant differences were seen in global health status, emotional functioning, social functioning, fatigue, nausea and vomiting, insomnia and appetite loss evolution in favour of the test group (p < 0.01). Both treatments were well tolerated.ConclusionOlanzapine can improve the complete response of delayed nausea and vomiting in patients receiving the highly or moderately emetogenic chemotherapy comparing with the standard therapy of antiemesis, as well as improve the QoL of the cancer patients during chemotherapy administration. Olanzapine is a safe and efficient drug for prevention of CINV.
The severe acute respiratory syndrome coronavirus 3C-like protease has been proposed to be a key target for structurally based drug design against SARS. The enzyme exists as a mixture of dimer and monomer, and only the dimer was considered to be active. In this report, we have investigated, using molecular dynamics simulation and mutational studies, the problems as to why only the dimer is active and whether both of the two protomers in the dimer are active. The molecular dynamics simulations show that the monomers are always inactive, that the two protomers in the dimer are asymmetric, and that only one protomer is active at a time. The enzyme activity of the hybrid severe acute respiratory syndrome coronavirus 3C-like protease of the wild-type protein and the inactive mutant proves that the dimerization is important for enzyme activity and only one active protomer in the dimer is enough for the catalysis. Our simulations also show that the right conformation for catalysis in one protomer can be induced upon dimer formation. These results suggest that the enzyme may follow the association, activation, catalysis, and dissociation mechanism for activity control.In early 2003, a highly epidemic disease named severe acute respiratory syndrome (SARS) 3 first broke out in China and then quickly spread to other circumjacent countries (1). Research proved that the nosogenesis was a novel coronavirus. In the coronavirus life cycle, 3C-like proteinase (3CL pro ) is important and indispensable and is a pivotal target in anti-SARS drug design (2). SARS 3CL pro shares 40 and 44% sequence identity to 3CL pro of human coronaviruses 229E and transmissible gastroenteritis virus, the crystal structures of which have been resolved (2, 3). Several homology models for SARS 3CL pro have been reported (2, 4, 5). More recently, the crystal structures of the enzyme and the inhibitor-enzyme complex have been determined (6 -11). All structures are very similar and consist of three domains. The first two domains form a chymotrypsin fold, and the third domain is an extra helix domain that plays an important role in dimerization and enzyme activity (12). All of the proteins are dimeric in the crystal structures, and there exists an equilibrium between the monomer and dimer in solution. In our previous work, we have observed that the activity increases with the increase of enzyme concentration, indicating the dimer is the active form of the proteinase (13). Other groups have studied the function of the N-finger in dimerization and enzyme activity. The N-terminal residues 1-5 delete transmissible gastroenteritis virus 3CL pro , and the N-terminal residues 1-7 delete SARS 3CL pro ; both have been reported to have no enzyme activities (3, 14 -16). Interestingly, Chen et al. (14) report that the N-finger deletion mutation does not affect the dimerization of SARS 3CLpro . Contrary to this, Hsu et al. (16) has found that the N-4 truncated protease is mainly monomeric and has little enzyme activity, but the N-3 truncated protease is almost the ...
The primary target of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) is epithelial cells in the respiratory and intestinal tract. The cellular receptor for SARS-CoV, angiotensin-converting enzyme 2 (ACE2), has been shown to be localized on the apical plasma membrane of polarized respiratory epithelial cells and to mediate infection from the apical side of these cells. Here, these results were confirmed and extended by including a colon carcinoma cell line (Caco-2), a lung carcinoma cell line (Calu-3) and Vero E6 cells in our analysis. All three cell types expressed human ACE2 on the apical membrane domain and were infected via this route, as determined with vesicular stomatitis virus pseudotypes containing the S protein of SARS-CoV. In a histological analysis of the respiratory tract, ACE2 was detected in the trachea, main bronchus and alveoli, and occasionally also in the small bronchi. These data will help us to understand the pathogenesis of SARS-CoV infection.Epithelia are a primary barrier to infection by microorganisms entering their host via body cavities such as the respiratory or intestinal tract (reviewed by Compans & Herrler, 2005). Epithelial cells are organized in a polarized fashion that involves the separation of the plasma membrane into an apical and a basolateral domain. The polarity of these cells affects both the early and late stages of infection, i.e. viruses may enter into and exit from a cell either via the apical membrane facing the external environment or via the basolateral membrane directed to the internal milieu of the organism. An important determinant of the virus infection is the presence of suitable receptors on the cell surface that allow attachment to and penetration through the plasma membrane. For viruses entering their host via the respiratory or gastrointestinal route, infection is understood most easily when the virus receptor is expressed on the apical surface.The primary target of the coronavirus associated with severe acute respiratory syndrome (SARS-CoV) is the respiratory tract. In addition to respiratory complications, some patients show intestinal symptoms, indicating that not only the respiratory but also the intestinal epithelium is susceptible to infection. It has been shown recently that the receptor for SARS-CoV, angiotensin-converting enzyme 2 (ACE2; Li et al., 2003;Wang et al., 2004), is localized on and mediates infection through the apical plasma membrane of respiratory epithelial cells (Jia et al., 2005;Sims et al., 2005; Tseng et al., 2005). On the other hand, ACE2 has been reported to be absent from enterocytes of the colon (Hamming et al., 2004), despite active replication of SARS-CoV in this portion of the intestine (Leung et al., 2003).To determine whether epithelial cells of different origin differ in the expression of ACE2, we included in our analysis three cell lines that form a highly polarized epithelial monolayer when grown on microporous filters: (i) Calu-3 (human lung carcinoma cells), (ii) Caco-2 (human colon carcinoma ce...
We have expressed a series of truncated spike (S) glycoproteins of SARS-CoV and found that the N-terminus 14-502 residuals were sufficient to bind to SARS-CoV susceptible Vero E6 cells. With this soluble S protein fragment as an affinity ligand, we screened HeLa cells transduced with retroviral cDNA library from Vero E6 cells and obtained a HeLa cell clone which could bind with the S protein. This cell clone was susceptible to HIV/SARS pseudovirus infection and the presence of a functional receptor for S protein in this cell clone was confirmed by the cell-cell fusion assay. Further studies showed the susceptibility of this cell was due to the expression of endogenous angiotensin-converting enzyme 2 (ACE2) which was activated by inserted LTR from retroviral vector used for expression cloning. When human ACE2 cDNA was transduced into NIH3T3 cells, the ACE2 expressing NIH3T3 cells could be infected with HIV/SARS pseudovirus. These data clearly demonstrated that ACE2 was the functional receptor for SARS-CoV.
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