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1.
Signal Transduct Target Ther ; 7(1): 137, 2022 04 25.
Article in English | MEDLINE | ID: covidwho-1805598

ABSTRACT

Whether and how innate antiviral response is regulated by humoral metabolism remains enigmatic. We show that viral infection induces progesterone via the hypothalamic-pituitary-adrenal axis in mice. Progesterone induces downstream antiviral genes and promotes innate antiviral response in cells and mice, whereas knockout of the progesterone receptor PGR has opposite effects. Mechanistically, stimulation of PGR by progesterone activates the tyrosine kinase SRC, which phosphorylates the transcriptional factor IRF3 at Y107, leading to its activation and induction of antiviral genes. SARS-CoV-2-infected patients have increased progesterone levels, and which are co-related with decreased severity of COVID-19. Our findings reveal how progesterone modulates host innate antiviral response, and point to progesterone as a potential immunomodulatory reagent for infectious and inflammatory diseases.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Antiviral Agents , COVID-19/genetics , Humans , Hypothalamo-Hypophyseal System , Immunity, Innate/genetics , Mice , Pituitary-Adrenal System , Progesterone/pharmacology
2.
Trends Immunol ; 43(3): 170-172, 2022 03.
Article in English | MEDLINE | ID: covidwho-1712717

ABSTRACT

The concurrent prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Middle East respiratory syndrome coronavirus (MERS-CoV) raises the concern for the emergence of potential new ß-CoV clades via genetic recombination, bearing high SARS-CoV-2-like transmissibility and high MERS-CoV-like mortality rates. Therefore, we argue that there is an urgent need to develop pan-ß-CoV vaccines that can target not only current SARS-CoV-2 variants of concern, but also future putative SARS-CoV-3- or MERS-CoV-2-like coronavirus.


Subject(s)
COVID-19 , Vaccines , COVID-19/prevention & control , COVID-19 Vaccines , Humans , SARS-CoV-2
3.
Chem Commun (Camb) ; 58(11): 1804-1807, 2022 Feb 03.
Article in English | MEDLINE | ID: covidwho-1639537

ABSTRACT

We present the finding of a dimeric ACE2 peptide mimetic designed through side chain cross-linking and covalent dimerization. It has a binding affinity of 16 nM for the SARS-CoV-2 spike RBD, and effectively inhibits the SARS-CoV-2 pseudovirus in Huh7-hACE2 cells with an IC50 of 190 nM and neutralizes the authentic SARS-CoV-2 in Caco2 cells with an IC50 of 2.4 µM. Our study should provide a new insight for the optimization of peptide-based anti-SARS-CoV-2 inhibitors.


Subject(s)
Antiviral Agents/pharmacology , Peptide Fragments/pharmacology , Peptidomimetics/pharmacology , SARS-CoV-2/drug effects , Amino Acid Sequence , Angiotensin-Converting Enzyme 2/chemistry , Antiviral Agents/chemical synthesis , Antiviral Agents/metabolism , Cell Line, Tumor , Humans , Microbial Sensitivity Tests , Peptide Fragments/chemical synthesis , Peptide Fragments/metabolism , Peptidomimetics/chemical synthesis , Peptidomimetics/metabolism , Protein Binding , Protein Domains , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism
4.
Cell ; 184(6): 1604-1620, 2021 03 18.
Article in English | MEDLINE | ID: covidwho-1392179

ABSTRACT

Historically, emerging viruses appear constantly and have cost millions of human lives. Currently, climate change and intense globalization have created favorable conditions for viral transmission. Therefore, effective antivirals, especially those targeting the conserved protein in multiple unrelated viruses, such as the compounds targeting RNA-dependent RNA polymerase, are urgently needed to combat more emerging and re-emerging viruses in the future. Here we reviewed the development of antivirals with common targets, including those against the same protein across viruses, or the same viral function, to provide clues for development of antivirals for future epidemics.


Subject(s)
Antiviral Agents/therapeutic use , Communicable Diseases, Emerging/drug therapy , Communicable Diseases, Emerging/epidemiology , Molecular Targeted Therapy/methods , Pandemics , Virus Diseases/drug therapy , Virus Diseases/epidemiology , Viruses/enzymology , Animals , Antiviral Agents/pharmacology , Communicable Diseases, Emerging/virology , Humans , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Viral Envelope Proteins/antagonists & inhibitors , Virus Diseases/virology , Virus Internalization/drug effects
7.
Acta Pharm Sin B ; 12(4): 1652-1661, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1336241

ABSTRACT

The development of broad-spectrum antivirals against human coronaviruses (HCoVs) is critical to combat the current coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants, as well as future outbreaks of emerging CoVs. We have previously identified a polyethylene glycol-conjugated (PEGylated) lipopeptide, EK1C4, with potent pan-CoV fusion inhibitory activity. However, PEG linkers in peptide or protein drugs may reduce stability or induce anti-PEG antibodies in vivo. Therefore, we herein report the design and synthesis of a series of dePEGylated lipopeptide-based pan-CoV fusion inhibitors featuring the replacement of the PEG linker with amino acids in the heptad repeat 2 C-terminal fragment (HR2-CF) of HCoV-OC43. Among these lipopeptides, EKL1C showed the most potent inhibitory activity against infection by SARS-CoV-2 and its spike (S) mutants, as well as other HCoVs and some bat SARS-related coronaviruses (SARSr-CoVs) tested. The dePEGylated lipopeptide EKL1C exhibited significantly stronger resistance to proteolytic enzymes, better metabolic stability in mouse serum, higher thermostability than the PEGylated lipopeptide EK1C4, suggesting that EKL1C could be further developed as a candidate prophylactic and therapeutic for COVID-19 and other coronavirus diseases.

8.
Cell Research ; 31(5):491-492, 2021.
Article in English | ProQuest Central | ID: covidwho-1208948
9.
Cell Res ; 31(5): 491-492, 2021 05.
Article in English | MEDLINE | ID: covidwho-1147838
13.
Nat Rev Microbiol ; 19(3): 211-219, 2021 03.
Article in English | MEDLINE | ID: covidwho-872709

ABSTRACT

The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has elicited an equally rapid response aiming to develop a COVID-19 vaccine. These efforts are encouraging; however, comprehensive efficacy and safety evaluations are essential in the development of a vaccine, and we can learn from previous vaccine development campaigns. In this Perspective, we summarize examples of vaccine-associated disease enhancement in the history of developing vaccines against respiratory syncytial virus, dengue virus, SARS-CoV and Middle East respiratory syndrome coronavirus, which highlight the importance of a robust safety and efficacy profile, and present recommendations for preclinical and clinical evaluation of COVID-19 vaccine candidates as well as for vaccine design and optimization.


Subject(s)
COVID-19 Vaccines , COVID-19/immunology , COVID-19/prevention & control , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/immunology , Clinical Trials as Topic , Drug Design , Drug Evaluation , Drug Industry , Humans , Respiratory Syncytial Virus Vaccines/immunology , Viral Vaccines/immunology
14.
Microbes Infect ; 22(6-7): 245-253, 2020.
Article in English | MEDLINE | ID: covidwho-351314

ABSTRACT

The global pandemic of COVID-19 caused by SARS-CoV-2 (also known as 2019-nCoV and HCoV-19) has posed serious threats to public health and economic stability worldwide, thus calling for development of vaccines against SARS-CoV-2 and other emerging and reemerging coronaviruses. Since SARS-CoV-2 and SARS-CoV have high similarity of their genomic sequences and share the same cellular receptor (ACE2), it is essential to learn the lessons and experiences from the development of SARS-CoV vaccines for the development of SARS-CoV-2 vaccines. In this review, we summarized the current knowledge on the advantages and disadvantages of the SARS-CoV vaccine candidates and prospected the strategies for the development of safe, effective and broad-spectrum coronavirus vaccines for prevention of infection by currently circulating SARS-CoV-2 and other emerging and reemerging coronaviruses that may cause future epidemics or pandemics.


Subject(s)
Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Severe Acute Respiratory Syndrome/prevention & control , Viral Vaccines/immunology , Animals , Betacoronavirus/genetics , COVID-19 , COVID-19 Vaccines , Coronavirus Infections/classification , Coronavirus Infections/immunology , Cross Protection , Humans , Pneumonia, Viral/immunology , SARS-CoV-2 , Severe Acute Respiratory Syndrome/immunology , Vaccines, Inactivated/immunology , Viral Vaccines/classification
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