Publications by authors named "Yinkai Duan"

6 Publications

  • Page 1 of 1

Structural basis for GTP-induced dimerization and antiviral function of guanylate-binding proteins.

Proc Natl Acad Sci U S A 2021 Apr;118(15)

School of Life Sciences, Tianjin University, Tianjin, 300072, China;

Guanylate-binding proteins (GBPs) form a family of dynamin-related large GTPases which mediate important innate immune functions. They were proposed to form oligomers upon GTP binding/hydrolysis, but the molecular mechanisms remain elusive. Here, we present crystal structures of C-terminally truncated human GBP5 (hGBP5), comprising the large GTPase (LG) and middle (MD) domains, in both its nucleotide-free monomeric and nucleotide-bound dimeric states, together with nucleotide-free full-length human GBP2. Upon GTP-loading, hGBP5 forms a closed face-to-face dimer. The MD of hGBP5 undergoes a drastic movement relative to its LG domain and forms extensive interactions with the LG domain and MD of the pairing molecule. Disrupting the MD interface (for hGBP5) or mutating the hinge region (for hGBP2/5) impairs their ability to inhibit HIV-1. Our results point to a GTP-induced dimerization mode that is likely conserved among all GBP members and provide insights into the molecular determinants of their antiviral function.
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http://dx.doi.org/10.1073/pnas.2022269118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054025PMC
April 2021

High-throughput screening identifies established drugs as SARS-CoV-2 PLpro inhibitors.

Protein Cell 2021 Apr 17. Epub 2021 Apr 17.

Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.

A new coronavirus (SARS-CoV-2) has been identified as the etiologic agent for the COVID-19 outbreak. Currently, effective treatment options remain very limited for this disease; therefore, there is an urgent need to identify new anti-COVID-19 agents. In this study, we screened over 6,000 compounds that included approved drugs, drug candidates in clinical trials, and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease (PLpro). Together with main protease (M), PLpro is responsible for processing the viral replicase polyprotein into functional units. Therefore, it is an attractive target for antiviral drug development. Here we discovered four compounds, YM155, cryptotanshinone, tanshinone I and GRL0617 that inhibit SARS-CoV-2 PLpro with IC values ranging from 1.39 to 5.63 μmol/L. These compounds also exhibit strong antiviral activities in cell-based assays. YM155, an anticancer drug candidate in clinical trials, has the most potent antiviral activity with an EC value of 170 nmol/L. In addition, we have determined the crystal structures of this enzyme and its complex with YM155, revealing a unique binding mode. YM155 simultaneously targets three "hot" spots on PLpro, including the substrate-binding pocket, the interferon stimulating gene product 15 (ISG15) binding site and zinc finger motif. Our results demonstrate the efficacy of this screening and repurposing strategy, which has led to the discovery of new drug leads with clinical potential for COVID-19 treatments.
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http://dx.doi.org/10.1007/s13238-021-00836-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052528PMC
April 2021

The main protease and RNA-dependent RNA polymerase are two prime targets for SARS-CoV-2.

Biochem Biophys Res Commun 2021 01 21;538:63-71. Epub 2020 Nov 21.

Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China. Electronic address:

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses an unprecedented global health crisis. It is particularly urgent to develop clinically effective therapies to contain the pandemic. The main protease (M) and the RNA-dependent RNA polymerase (RdRP), which are responsible for the viral polyprotein proteolytic process and viral genome replication and transcription, respectively, are two attractive drug targets for SARS-CoV-2. This review summarizes up-to-date progress in the structural and pharmacological aspects of those two key targets above. Different classes of inhibitors individually targeting M and RdRP are discussed, which could promote drug development to treat SARS-CoV-2 infection.
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http://dx.doi.org/10.1016/j.bbrc.2020.10.091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680044PMC
January 2021

Structural basis for the inhibition of SARS-CoV-2 main protease by antineoplastic drug carmofur.

Nat Struct Mol Biol 2020 06 7;27(6):529-532. Epub 2020 May 7.

Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China.

The antineoplastic drug carmofur is shown to inhibit the SARS-CoV-2 main protease (M). Here, the X-ray crystal structure of M in complex with carmofur reveals that the carbonyl reactive group of carmofur is covalently bound to catalytic Cys145, whereas its fatty acid tail occupies the hydrophobic S2 subsite. Carmofur inhibits viral replication in cells (EC = 24.30 μM) and is a promising lead compound to develop new antiviral treatment for COVID-19.
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http://dx.doi.org/10.1038/s41594-020-0440-6DOI Listing
June 2020

Structure of M from SARS-CoV-2 and discovery of its inhibitors.

Nature 2020 06 9;582(7811):289-293. Epub 2020 Apr 9.

Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China.

A new coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the aetiological agent responsible for the 2019-2020 viral pneumonia outbreak of coronavirus disease 2019 (COVID-19). Currently, there are no targeted therapeutic agents for the treatment of this disease, and effective treatment options remain very limited. Here we describe the results of a programme that aimed to rapidly discover lead compounds for clinical use, by combining structure-assisted drug design, virtual drug screening and high-throughput screening. This programme focused on identifying drug leads that target main protease (M) of SARS-CoV-2: M is a key enzyme of coronaviruses and has a pivotal role in mediating viral replication and transcription, making it an attractive drug target for SARS-CoV-2. We identified a mechanism-based inhibitor (N3) by computer-aided drug design, and then determined the crystal structure of M of SARS-CoV-2 in complex with this compound. Through a combination of structure-based virtual and high-throughput screening, we assayed more than 10,000 compounds-including approved drugs, drug candidates in clinical trials and other pharmacologically active compounds-as inhibitors of M. Six of these compounds inhibited M, showing half-maximal inhibitory concentration values that ranged from 0.67 to 21.4 μM. One of these compounds (ebselen) also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of our screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases for which no specific drugs or vaccines are available.
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http://dx.doi.org/10.1038/s41586-020-2223-yDOI Listing
June 2020