SARS-CoV-2 is the underlying cause for the COVID-19 pandemic. Like most enveloped RNA viruses, SARS-CoV-2 uses a homotrimeric surface antigen to gain entry into host cells. Here we describe S-Trimer, ...a native-like trimeric subunit vaccine candidate for COVID-19 based on Trimer-Tag technology. Immunization of S-Trimer with either AS03 (oil-in-water emulsion) or CpG 1018 (TLR9 agonist) plus alum adjuvants induced high-level of neutralizing antibodies and Th1-biased cellular immune responses in animal models. Moreover, rhesus macaques immunized with adjuvanted S-Trimer were protected from SARS-CoV-2 challenge compared to vehicle controls, based on clinical observations and reduction of viral loads in lungs. Trimer-Tag may be an important platform technology for scalable production and rapid development of safe and effective subunit vaccines against current and future emerging RNA viruses.
The 2019 novel coronavirus (SARS-CoV-2) outbreak is a major challenge for public health. SARS-CoV-2 infection in human has a broad clinical spectrum ranging from mild to severe cases, with a ...mortality rate of ~6.4% worldwide (based on World Health Organization daily situation report). However, the dynamics of viral infection, replication and shedding are poorly understood. Here, we show that Rhesus macaques are susceptible to the infection by SARS-CoV-2. After intratracheal inoculation, the first peak of viral RNA was observed in oropharyngeal swabs one day post infection (1 d.p.i.), mainly from the input of the inoculation, while the second peak occurred at 5 d.p.i., which reflected on-site replication in the respiratory tract. Histopathological observation shows that SARS-CoV-2 infection can cause interstitial pneumonia in animals, characterized by hyperemia and edema, and infiltration of monocytes and lymphocytes in alveoli. We also identified SARS-CoV-2 RNA in respiratory tract tissues, including trachea, bronchus and lung; and viruses were also re-isolated from oropharyngeal swabs, bronchus and lung, respectively. Furthermore, we demonstrated that neutralizing antibodies generated from the primary infection could protect the Rhesus macaques from a second-round challenge by SARS-CoV-2. The non-human primate model that we established here provides a valuable platform to study SARS-CoV-2 pathogenesis and to evaluate candidate vaccines and therapeutics.
Human immunodeficiency virus (HIV) infection is fast becoming widespread in the world with 37.7 million people living with HIV in 2020. Antiretroviral therapy involving chemical drugs has declined ...acquired immunodeficiency syndrome (AIDS)‐related mortality and improved the life quality of AIDS/HIV sufferers. However, the emergence of drug resistance and side effects are the main obstacles for the long‐term use of these chemicals as antiretroviral therapy. Recently, a lot of emphasis is being put on finding naturally occurring drug candidates that show activity against HIV and can be potentially used as antiretroviral therapy. In this study, different medicinal plants, Pistacia khinjuk, Teucrium stocksianum, Uncaria tomentosa, Pistacia integerrima, Trigonella gharuensis, and Artocarpus lakoocha, were explored for their anti‐HIV potential. Syncytium and p24 assays were performed to determine antiviral activity, while the MTT assay was used to determine cytotoxicity. Results showed that extracts from all six plants inhibited HIV replication in vitro. Also, extracts from Pistacia khinjuk, Teucrium stocksianum, Uncaria tomentosa, and Pistacia integerrima showed low cytotoxicity with a 50% cytotoxicity concentration value of >200 μM. Results of this study indicate that there is potential in these natural extracts to become candidate drugs to be used as complementary and alternative medicine for HIV infection.
Highlights
Important findings with reference to anti‐human immunodeficiency virus (HIV) activities and cytotoxicities of extracts from six different plants.
Extracts from all six plants inhibited HIV replication in vitro.
Pistacia khinjuk (concentration required for the effectiveness of 50% EC50 = 0.34 µM) and Teucrium stocksianum (EC50 = 0.57 µM) showed the highest anti‐HIV activities.
These natural extracts have the potential to become candidate drugs to be used as a complementary and alternative medicine for HIV.
The petrogenesis of the isolated pegmatites from granites is under debate. In the Chinese Altai, massive isolated pegmatites have been regarded as derivatives of granitic melts, which contradicts to ...the results of recent studies. In this work, the geology and mineralogy, as well as the zircon U-Pb chronology and Hf isotope geochemistry, of 10 Permian pegmatites are analyzed, and a comparative study of the Permian pegmatites and granites is conducted to reveal the petrogenesis of the Permian pegmatites in the Chinese Altai. The Permian pegmatites are concentrated in the Qiongkuer domain with a linear distribution and show structural control from regional anticlinoriums and connections to adjacent migmatites and luecogranite dykes. Their zircon U-Pb ages are 274–253 Ma, with the dominating age being late Permian. The pegmatites have three mineralization types including Li-Be-Ta-Nb ± Sn, Be-Nb-Ta ± REEs (rare earth elements) and REEs. The former two are comparable with the Triassic and Devonian-Carboniferous pegmatites in mineralization and Hf isotope composition, respectively, and the latter is unique in the Permian generation. The Permian pegmatites have comparable Hf isotope compositions with the juvenile and specific components in the Habahe Group, which indicates the dependency of mineralization on source from the heterogeneous Habahe Group metasedimentary rocks. The pegmatites also show decoupling spatial-temporal and differentiation-source correlations with the Permian granites, indicating no genetic relationship between them. Combining with the Permian high temperature metamorphism and previous tectonic-magmatic-metamorphic studies, we suggest that the Permian rare metal/earth pegmatites were likely generated by anatexis of the Habahe Group metasedimentary rocks under an extensional setting after the arc-arc collision between the Junggar arcs and the Chinese Altai.
•The Permian pegmatites in the Chinese Altai formed mainly during late Permian.•The pegmatites have three mineralization types including Li-Be-Ta-Nb ± Sn, Be-Nb-Ta ± REEs and REEs.•The mineralization types of the pegmatites show dependencies on source and partial meting degrees of source.•The pegmatites show decoupling spatial-temporal-differentiation-source correlations to the Permian granites.•The pegmatites were likely generated by anatexis of metasedimentary rocks after arc-arc collision.
Nucleos(t)ide analogues (NAs) have been widely used for the treatment of chronic hepatitis B (CHB). Because viral DNA polymerase lacks proofreading function (3′ exonuclease activity), theoretically, ...the incorporated NAs would irreversibly terminate viral DNA synthesis. This study explored the natures of nascent hepatitis B virus (HBV) DNA and infectivity of progeny virions produced under NA treatment. HBV infectivity was determined by infection of HepG2‐NTCP cells and primary human hepatocytes (PHHs). Biochemical properties of HBV DNA in the progeny virions were investigated by qPCR, northern blotting, or Southern blotting hybridization, sucrose gradient centrifugation, and in vitro endogenous DNA polymerase assay. Progeny HBV virions produced under NA treatment were mainly not infectious to HepG2‐NTCP cells or PHHs. Biochemical analysis revealed that under NA treatment, HBV DNA in nucleaocapsids or virions were predominantly short minus‐strand DNA with irreversible termination. This finding was supported by the observation of first disappearance of relaxed circular DNA and then the proportional decline of HBV‐DNA levels corresponding to the regions of PreC/C, S, and X genes in serial sera of patients receiving NA treatment. Conclusion: HBV virions produced under NA treatment are predominantly replication deficient because the viral genomes are truncated and elongation of DNA chains is irreversibly terminated. Clinically, our results suggest that the viral loads of CHB patients under NA therapy vary with the different regions of genome being detected by qPCR assays. Our findings also imply that NA prevention of perinatal and sexual HBV transmission as well as infection of transplanted livers works not only by reducing viral loads, but also by producing noninfectious virions.
Naturally abundant quinones are important molecules, which play essential roles in various biological processes due to their reduction potential. In contrast to their universality, the investigation ...of reactions between quinones and proteins remains sparse. Herein, we report the development of a convenient strategy to protein modification via a biomimetic quinone-mediated oxidation at the N-terminus. By exploiting unique reactivity of an ortho-quinone reagent, the α-amine of protein N-terminus is oxidized to generate aldo or keto handle for orthogonal conjugation. The applications have been demonstrated using a range of proteins, including myoglobin, ubiquitin and small ubiquitin-related modifier 2 (SUMO2). The effect of this method is further highlighted via the preparation of a series of 17 macrophage inflammatory protein 1β (MIP-1β) analogs, followed by preliminary anti-HIV activity and cell viability assays, respectively. This method offers an efficient and complementary approach to existing strategies for N-terminal modification of proteins.
In this study, a novel strategy is developed for the first time, referred to as high‐concentration cobalt ion‐assisted hydration (HCCAH) utilizing zeolitic imidazolate framework‐67 (ZIF‐67) as a ...precursor, to produce independent and flat α‐cobalt hydroxide nanosheets (CHN). These nanosheets offer abundant contact sites for binding with virus surface proteins. The formation of CHN involves the in situ transformation from ZIF‐67, due to the matching of the hydrolysis rate of ZIF‐67 and in situ growth rate of cobalt hydroxide orchestrated by high concentration of cobalt ions. Notably, the CHN contains a higher proportion of trivalent cobalt, which is shown to enhance the binding with the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2) Spike protein and induce protein structural denaturation, as demonstrated by molecular dynamics (MD) simulation. Antiviral experiments using pseudovirus and authentic viruses have confirmed the promising antiviral performance of CHN. Furthermore, both in vitro and in vivo experiments have demonstrated the excellent biocompatibility of CHN. This research opens up new possibilities for the application of cobalt hydroxide nanosheets and serves as a valuable reference for the design of antiviral nanomaterials.
ZIF‐67 derived α‐Co(OH)2 2D nanosheets are developed through an innovative high‐concentration cobalt ion‐assisted hydration method. These nanosheets possess a high proportion of trivalent cobalt ions and exhibit independent and flat morphology. They effectively prevent SARS‐CoV‐2 virus infection of cells, since they have extremely high affinity to the spike protein receptor‐binding domain (RBD) of the virus.
Circular RNAs (circRNAs) are abundant in mammalian brain and some show age-dependent expression patterns. Here, we report that circGRIA1, a conserved circRNA isoform derived from the genomic loci of ...α-mino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunit Gria1, shows an age-related and male-specific increase in expression in the rhesus macaque prefrontal cortex and hippocampus. We show circGRIA1 is predominantly localized to the nucleus, and find an age-related increase in its association with the promoter region of Gria1 gene, suggesting it has a regulatory role in Gria1 transcription. In vitro and in vivo manipulation of circGRIA1 negatively regulates Gria1 mRNA and protein levels. Knockdown of circGRIA1 results in an age-related improvement of synaptogenesis, and GluR1 activity-dependent synaptic plasticity in the hippocampal neurons in males. Our findings underscore the importance of circRNA regulation and offer an insight into the biology of brain aging.
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic worldwide. Currently, however, no effective drug or vaccine is available to treat or prevent the ...resulting coronavirus disease 2019 (COVID-19). Here, we report our discovery of a promising anti-COVID-19 drug candidate, the lipoglycopeptide antibiotic dalbavancin, based on virtual screening of the FDA-approved peptide drug library combined with in vitro and in vivo functional antiviral assays. Our results showed that dalbavancin directly binds to human angiotensin-converting enzyme 2 (ACE2) with high affinity, thereby blocking its interaction with the SARS-CoV-2 spike protein. Furthermore, dalbavancin effectively prevents SARS-CoV-2 replication in Vero E6 cells with an EC
of ~12 nM. In both mouse and rhesus macaque models, viral replication and histopathological injuries caused by SARS-CoV-2 infection are significantly inhibited by dalbavancin administration. Given its high safety and long plasma half-life (8-10 days) shown in previous clinical trials, our data indicate that dalbavancin is a promising anti-COVID-19 drug candidate.
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