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1.
Viruses ; 13(11)2021 10 20.
Article in English | MEDLINE | ID: covidwho-1538532

ABSTRACT

Over the course of human history, billions of people worldwide have been infected by various viruses. Despite rapid progress in the development of biomedical techniques, it is still a significant challenge to find promising new antiviral targets and drugs. In the past, antiviral drugs mainly targeted viral proteins when they were used as part of treatment strategies. Since the virus mutation rate is much faster than that of the host, such drugs feature drug resistance and narrow-spectrum antiviral problems. Therefore, the targeting of host molecules has gradually become an important area of research for the development of antiviral drugs. In recent years, rapid advances in high-throughput sequencing techniques have enabled numerous genetic studies (such as genome-wide association studies (GWAS), clustered regularly interspersed short palindromic repeats (CRISPR) screening, etc.) for human diseases, providing valuable genetic and evolutionary resources. Furthermore, it has been revealed that successful drug targets exhibit similar genetic and evolutionary features, which are of great value in identifying promising drug targets and discovering new drugs. Considering these developments, in this article the authors propose a host-targeted antiviral drug discovery strategy based on knowledge of genetics and evolution. We first comprehensively summarized the genetic, subcellular location, and evolutionary features of the human genes that have been successfully used as antiviral targets. Next, the summarized features were used to screen novel druggable antiviral targets and to find potential antiviral drugs, in an attempt to promote the discovery of new antiviral drugs.


Subject(s)
Antiviral Agents/pharmacology , Virus Diseases/virology , Viruses/drug effects , Viruses/genetics , Animals , Antiviral Agents/chemistry , Drug Discovery , Genome-Wide Association Study , Humans , Viral Proteins/genetics , Viral Proteins/metabolism , Virus Diseases/drug therapy , Viruses/metabolism
2.
Preprint in English | bioRxiv | ID: ppbiorxiv-393629

ABSTRACT

Receptor recognition and subsequent membrane fusion are essential for the establishment of successful infection by SARS-CoV-2. Halting these steps can cure COVID-19. Here we have identified and characterized a potent human monoclonal antibody, HB27, that blocks SARS-CoV-2 attachment to its cellular receptor at sub-nM concentrations. Remarkably, HB27 can also prevent SARS-CoV-2 membrane fusion. Consequently, a single dose of HB27 conferred effective protection against SARS-CoV-2 in two established mouse models. Rhesus macaques showed no obvious adverse events when administrated with 10-fold of effective dose of HB27. Cryo-EM studies on complex of SARS-CoV-2 trimeric S with HB27 Fab reveal that three Fab fragments work synergistically to occlude SARS-CoV-2 from binding to ACE2 receptor. Binding of the antibody also restrains any further conformational changes of the RBD, possibly interfering with progression from the prefusion to the postfusion stage. These results suggest that HB27 is a promising candidate for immuno-therapies against COVID-19. HighlightsO_LISARS-CoV-2 specific antibody, HB27, blocks viral receptor binding and membrane fusion C_LIO_LIHB27 confers prophylactic and therapeutic protection against SARS-CoV-2 in mice models C_LIO_LIRhesus macaques showed no adverse side effects when administered with HB27 C_LIO_LICryo-EM studies suggest that HB27 sterically occludes SARS-CoV-2 from its receptor C_LI

3.
Preprint in English | bioRxiv | ID: ppbiorxiv-377333

ABSTRACT

The ongoing SARS-CoV-2 pandemic has brought an urgent need for animal models to study the pathogenicity of the virus. Herein, we generated and characterized a novel mouse-adapted SARS-CoV-2 strain, named MASCp36, that causes severe acute respiratory symptoms and mortality in standard laboratory mice. Particularly, this model exhibits age and gender related skewed distribution of mortality akin to severe COVID-19, and the 50% lethal dose (LD50) of MASCp36 was 58 PFU in 9-month-old, male BALB/c mice. Deep sequencing identified three amino acid substitutions, N501Y, Q493H, and K417N, subsequently emerged at the receptor binding domain (RBD) of MASCp36, during in vivo passaging. All three mutations in RBD significantly enhanced the binding affinity to its endogenous receptor, mouse ACE2 (mACE2). Cryo-electron microscopy (cryo-EM) analysis of human ACE2 (hACE2) or mACE2 in complex with the RBD of MASCp36 at 3.1 to 3.7 angstrom resolution elucidates molecular basis for the receptor-binding switch driven by specific amino acid substitutions. Interestingly, N501Y and Q493H enhanced the binding affinity to human ACE2 (hACE2); while triple mutations N501Y/Q493H/K417N decreased affinity to hACE2, thus led to the reduced infectivity of MASCp36 to human cells. Our study not only provides a robust platform for studying the pathogenesis of severe COVID-19 and rapid evaluation of coutermeasures against SARS-CoV-2, but also unveils the molecular mechanism for the rapid adaption and evolution of SARS-CoV-2 in human and animals. One sentence summaryA mouse adapted SARS-CoV-2 strain that harbored specific amino acid substitutions in the RBD of S protein showed 100% mortality in aged, male BALB/c mice.

4.
Preprint in English | bioRxiv | ID: ppbiorxiv-376673

ABSTRACT

Olfactory dysfunction caused by SARS-CoV-2 infection represents as one of the most predictive and common symptoms in COVID-19 patients. However, the causal link between SARS-CoV-2 infection and olfactory disorders remains lacking. Herein we demonstrate intranasal inoculation of SARS-CoV-2 induces robust viral replication in the olfactory epithelium (OE), resulting in transient olfactory dysfunction in humanized ACE2 mice. The sustentacular cells and Bowmans gland cells in OE were identified as the major targets of SARS-CoV-2 before the invasion into olfactory sensory neurons. Remarkably, SARS-CoV-2 infection triggers cell death and immune cell infiltration, and impairs the uniformity of OE structure. Combined transcriptomic and proteomic analyses reveal the induction of antiviral and inflammatory responses, as well as the downregulation of olfactory receptors in OE from the infected animals. Overall, our mouse model recapitulates the olfactory dysfunction in COVID-19 patients, and provides critical clues to understand the physiological basis for extrapulmonary manifestations of COVID-19.

5.
Preprint in English | bioRxiv | ID: ppbiorxiv-354563

ABSTRACT

Infections with zoonotic viruses, such as flaviviruses, influenza virus, and the SARS-CoV-2 pandemic coronavirus constitute an increasing global risk. Hence, an urgent need exists for the development of broad-spectrum antivirals to prevent such outbreaks. Here, we show that the maduramycin and CP-80,219 aglycone polyether ionophores exhibit effective broad-spectrum antiviral activity, against various viruses, including Japanese encephalitis virus (JEV), Dengue virus (DENV), Zika virus (ZIKV), and Chikungunya virus (CHIKV), while also exhibiting promising activity against PR8 influenza virus and SARS-CoV-2. Moreover, liposome-encapsulated maduramycin and CP-80,219 provide full protection for mice from infection with JEV in vivo. Mechanistic studies suggest that aglycone polyether ionophores primarily inhibit the viral replication step without blocking endosome acidification to promote the fusion between viral and cellular membranes. The successful application of liposomes containing aglycone polyether ionophores in JEV-infected mice offers hope to the development of broad-spectrum antiviral drugs like penicillin back to 1940s.

6.
Preprint in English | bioRxiv | ID: ppbiorxiv-309294

ABSTRACT

Mutations and transient conformational movements of receptor binding domain (RBD) that make neutralizing epitopes momentarily unavailable, present immune escape routes to SARS-CoV-2. To mitigate viral escape, we developed a cocktail of neutralizing antibodies (NAbs) targeting epitopes located on different domains of spike (S) protein. Screening of a library of monoclonal antibodies generated from peripheral blood mononuclear cells of COVID-19 convalescent patients yielded potent NAbs, targeting N-terminal domain (NTD) and RBD domain of S, effective at nM concentrations. Remarkably, combination of RBD-targeting NAbs and NTD-binding NAb, FC05, dramatically enhanced the neutralization potency in cell-based assays and animal model. Results of competitive SPR assays and cryo-EM structures of Fabs bound to S unveil determinants of immunogenicity. Combinations of immunogens, identified in NTD and RBD of S, when immunized in rabbits elicited potent protective immune responses against SARS-CoV-2. These results provide a proof-of-concept for neutralization-based immunogen design targeting SARS-CoV-2 NTD and RBD. One sentence summaryImmunogens identified in the NTD and RBD of the SARS-CoV-2 spike protein using a cocktail of non-competing NAbs when injected in rabbits elicited a potent protective immune response against SARS-CoV-2.

7.
Preprint in English | medRxiv | ID: ppmedrxiv-20171371

ABSTRACT

The World Health Organization has declared SARS-CoV-2 virus outbreak a world-wide pandemic. Individuals infected by the virus exhibited different degrees of symptoms, the basis of which remains largely unclear. Currently, though convalescent individuals have been shown with both cellular and humoral immune responses, there is very limited understanding on the immune responses, especially adaptive immune responses, in patients with severe COVID-19. Here, we examined 10 blood samples from COVID-19 patients with acute respiratory distress syndrome (ARDS). The majority of them (70%) mounted SARS-CoV-2-specific humoral immunity with production of neutralizing antibodies. However, compared to healthy controls, the percentages and absolute numbers of both NK cells and CD8+ T cells were significantly reduced, accompanied with decreased IFN{gamma} expression in CD4+ T cells in peripheral blood from severe patients. Most notably, we failed in detecting SARS-CoV-2-specific IFN{gamma} production by peripheral blood lymphocytes from these patients. Our work thus indicates that COVID-19 patients with severe symptoms are associated with defective cellular immunity, which not only provides insights on understanding the pathogenesis of COVID-19, but also has implications in developing an effective vaccine to SARS-CoV-2.

8.
Preprint in English | bioRxiv | ID: ppbiorxiv-129098

ABSTRACT

The COVID-19 pandemic caused by the SARS-CoV-2 virus has resulted in an unprecedented public health crisis. There are no approved vaccines or therapeutics for treating COVID-19. Here we reported a humanized monoclonal antibody, H014, efficiently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2 at nM level by engaging the S receptor binding domain (RBD). Importantly, H014 administration reduced SARS-CoV-2 titers in the infected lungs and prevented pulmonary pathology in hACE2 mouse model. Cryo-EM characterization of the SARS-CoV-2 S trimer in complex with the H014 Fab fragment unveiled a novel conformational epitope, which is only accessible when the RBD is in open conformation. Biochemical, cellular, virological and structural studies demonstrated that H014 prevents attachment of SARS-CoV-2 to its host cell receptors. Epitope analysis of available neutralizing antibodies against SARS-CoV and SARS-CoV-2 uncover broad cross-protective epitopes. Our results highlight a key role for antibody-based therapeutic interventions in the treatment of COVID-19. One sentence summaryA potent neutralizing antibody conferred protection against SARS-CoV-2 in an hACE2 humanized mouse model by sterically blocking the interaction of the virus with its receptor.

9.
Chinese Journal of Laboratory Medicine ; (12): E011-E011, 2020.
Article in Chinese | WPRIM (Western Pacific), WPRIM (Western Pacific) | ID: covidwho-2083

ABSTRACT

Laboratory testing plays an important role in the diagnosis and treatment of patients with Novel Coronavirus pneumonia. However, the lack of understanding of the virus in the early stage led to great difficulties in biosafety protection for clinical laboratories. Based on the latest researches and findings about the virus, this paper provides some personal opinions on the biosafety prevention in clinical laboratorians under epidemic condition for the reference of laboratory workers.

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