Rxivist logo

Rxivist.org combines preprints from bioRxiv.org with data from Twitter to help you find the papers being discussed in your field.
Currently indexing 93,254 bioRxiv papers from 397,991 authors.

Most downloaded bioRxiv papers, all time

Results 1 through 20 out of 3091

in category biochemistry

 

1: Structure of Mpro from COVID-19 virus and discovery of its inhibitors

Zhenming Jin, Xiaoyu Du et al.

20,429 downloads (posted 27 Feb 2020)

A new coronavirus (CoV) identified as COVID-19 virus is the etiological agent responsible for the 2019-2020 viral pneumonia outbreak that commenced in Wuhan[1][1]–[4][2]. Currently there is no targeted therapeutics and effective treatment options remain very limited. In order to rapidly discover lead compounds for clinical use, we initiated a program of combined structure-assisted drug design, virtual drug screening and high-throughput screening to identify new drug leads that target the COVID-19 virus main protease (Mpro). Mpro is a key CoV enzyme, which plays a pivotal role in mediating viral replication and transcription, making it an attractive drug target for this virus[5][3],[6][4]. Here, we identified a mechanism-based inhibitor, N3, by computer-aided drug design and subsequently determined the crystal structure of COVID-19 virus Mpro in complex with this compound. Next, through a combination of structure-based virtual and high-throughput screening, we assayed over 10,000 compounds including approved drugs, drug candidates in clinical trials, and other pharmacologically active compounds as inhibitors of Mpro. Six of these inhibit Mpro with IC50 values ranging from 0.67 to 21.4 μM. Ebselen also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of this screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases where no specific drugs or vaccines are available. [1]: #ref-1 [2]: #ref-4 [3]: #ref-5 [4]: #ref-6

https://rxivist.org/papers/75107
https://doi.org/10.1101/2020.02.26.964882

2: Structure, function and antigenicity of the SARS-CoV-2 spike glycoprotein

Alexandra C. Walls, Young-Jun Park et al.

13,165 downloads (posted 20 Feb 2020)

The recent emergence of a novel coronavirus associated with an ongoing outbreak of pneumonia (Covid-2019) resulted in infections of more than 72,000 people and claimed over 1,800 lives. Coronavirus spike (S) glycoprotein trimers promote entry into cells and are the main target of the humoral immune response. We show here that SARS-CoV-2 S mediates entry in VeroE6 cells and in BHK cells transiently transfected with human ACE2, establishing ACE2 as a functional receptor for this novel coronavirus. We further demonstrate t...

https://rxivist.org/papers/74487
https://doi.org/10.1101/2020.02.19.956581

3: Structure of dimeric full-length human ACE2 in complex with B0AT1

Renhong Yan, Yuanyuan Zhang et al.

12,089 downloads (posted 18 Feb 2020)

Angiotensin-converting enzyme 2 (ACE2) is the surface receptor for SARS coronavirus (SARS-CoV) through interaction with its spike glycoprotein (S protein). ACE2 is also suggested to be the receptor for the new coronavirus (2019-nCoV), which is causing a serious epidemic in China manifested with severe respiratory syndrome. BAT1 (SLC6A19) is a neutral amino acid transporter whose surface expression in intestinal cells requires ACE2. Here we present the 2.9 Å resolution cryo-EM structure of full-length human ACE2 in compl...

https://rxivist.org/papers/74225
https://doi.org/10.1101/2020.02.17.951848

4: Substrate specificity profiling of SARS-CoV-2 main protease enables design of activity-based probes for patient-sample imaging

Wioletta Rut, Katarzyna Groborz et al.

11,115 downloads (posted 08 Mar 2020)

In December 2019, the first cases of infection with a novel coronavirus, SARS-CoV-2, were diagnosed in Wuhan, China. Due to international travel and human-to-human transmission, the virus spread rapidly inside and outside of China. Currently, there is no effective antiviral treatment for coronavirus disease 2019 (COVID-19); therefore, research efforts are focused on the rapid development of vaccines and antiviral drugs. The SARS-CoV-2 main protease constitutes one of the most attractive antiviral drug targets. To addres...

https://rxivist.org/papers/76197
https://doi.org/10.1101/2020.03.07.981928

5: The 2019 coronavirus (SARS-CoV-2) surface protein (Spike) S1 Receptor Binding Domain undergoes conformational change upon heparin binding.

Courtney Mycroft-West, Dunhao Su et al.

9,249 downloads (posted 02 Mar 2020)

Many pathogens take advantage of the dependence of the host on the interaction of hundreds of extracellular proteins with the glycosaminoglycans heparan sulphate to regulate homeostasis and use heparan sulphate as a means to adhere and gain access to cells. Moreover, mucosal epithelia such as that of the respiratory tract are protected by a layer of mucin polysaccharides, which are usually sulphated. Consequently, the polydisperse, natural products of heparan sulphate and the allied polysaccharide, heparin have been fou...

https://rxivist.org/papers/75414
https://doi.org/10.1101/2020.02.29.971093

6: Structure of RNA-dependent RNA polymerase from 2019-nCoV, a major antiviral drug target

Yan Gao, Liming Yan et al.

8,927 downloads (posted 17 Mar 2020)

A novel coronavirus (2019-nCoV) outbreak has caused a global pandemic resulting in tens of thousands of infections and thousands of deaths worldwide. The RNA-dependent RNA polymerase (RdRp, also named nsp12), which catalyzes the synthesis of viral RNA, is a key component of coronaviral replication/transcription machinery and appears to be a primary target for the antiviral drug, remdesivir. Here we report the cryo-EM structure of 2019-nCoV full-length nsp12 in complex with cofactors nsp7 and nsp8 at a resolution of 2.9-...

https://rxivist.org/papers/76979
https://doi.org/10.1101/2020.03.16.993386

7: The sequence of human ACE2 is suboptimal for binding the S spike protein of SARS coronavirus 2

Erik Procko

8,681 downloads (posted 17 Mar 2020)

The rapid and escalating spread of SARS coronavirus 2 (SARS-CoV-2) poses an immediate public health emergency. The viral spike protein S binds ACE2 on host cells to initiate molecular events that release the viral genome intracellularly. Soluble ACE2 inhibits entry of both SARS and SARS-2 coronaviruses by acting as a decoy for S binding sites, and is a candidate for therapeutic, prophylactic and diagnostic development. Using deep mutagenesis, variants of ACE2 are identified with increased binding to the receptor binding...

https://rxivist.org/papers/76977
https://doi.org/10.1101/2020.03.16.994236

8: Structural basis for the recognition of the 2019-nCoV by human ACE2

Renhong Yan, Yuanyuan Zhang et al.

7,866 downloads (posted 20 Feb 2020)

Angiotensin-converting enzyme 2 (ACE2) has been suggested to be the cellular receptor for the new coronavirus (2019-nCoV) that is causing the coronavirus disease 2019 (COVID-19). Like other coronaviruses such as the SARS-CoV, the 2019-nCoV uses the receptor binding domain (RBD) of the surface spike glycoprotein (S protein) to engage ACE2. We most recently determined the structure of the full-length human ACE2 in complex with a neutral amino acid transporter BAT1. Here we report the cryo-EM structure of the full-length h...

https://rxivist.org/papers/74465
https://doi.org/10.1101/2020.02.19.956946

9: Homology Directed Repair by Cas9:Donor Co-localization in Mammalian Cells

Philip JR Roche, Heidi Gytz et al.

7,162 downloads (posted 16 Jan 2018)

Homology directed repair (HDR) induced by site specific DNA double strand breaks (DSB) with CRISPR/Cas9 is a precision gene editing approach that occurs at low frequency in comparison to indel forming non homologous end joining (NHEJ). In order to obtain high HDR percentages in mammalian cells, we engineered Cas9 protein fused to a high-affinity monoavidin domain to deliver biotinylated donor DNA to a DSB site. In addition, we used the cationic polymer, polyethylenimine, to deliver Cas9 RNP-donor DNA complex into the ce...

https://rxivist.org/papers/10776
https://doi.org/10.1101/248179

10: Heparin inhibits cellular invasion by SARS-CoV-2: structural dependence of the interaction of the surface protein (spike) S1 receptor binding domain with heparin.

Courtney J. Mycroft-West, Dunhao Su et al.

7,103 downloads (posted 28 Apr 2020)

The dependence of the host on the interaction of hundreds of extracellular proteins with the cell surface glycosaminoglycan heparan sulphate (HS) for the regulation of homeostasis is exploited by many microbial pathogens as a means of adherence and invasion. The closely related polysaccharide heparin, the widely used anticoagulant drug, which is structurally similar to HS and is a common experimental proxy, can be expected to mimic the properties of HS. Heparin prevents infection by a range of viruses if added exogenous...

https://rxivist.org/papers/81529
https://doi.org/10.1101/2020.04.28.066761

11: Molecular Modeling Evaluation of the Binding Effect of Ritonavir, Lopinavir and Darunavir to Severe Acute Respiratory Syndrome Coronavirus 2 Proteases

Shen Lin, Runnan Shen et al.

6,513 downloads (posted 03 Feb 2020)

Three anti-HIV drugs, ritonavir, lopinavir and darunavir, might have therapeutic effect on coronavirus disease 2019 (COVID-19). In this study, the structure models of two severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteases, coronavirus endopeptidase C30 (CEP\_C30) and papain like viral protease (PLVP), were built by homology modeling. Ritonavir, lopinavir and darunavir were then docked to the models, respectively, followed by energy minimization of the protease-drug complexes. In the simulations, rito...

https://rxivist.org/papers/72778
https://doi.org/10.1101/2020.01.31.929695

12: CRISPR/Cas9-APEX-mediated proximity labeling enables discovery of proteins associated with a predefined genomic locus in living cells

Samuel A. Myers, Jason Wright et al.

6,114 downloads (posted 04 Jul 2017)

The activation or repression of a gene's expression is primarily controlled by changes in the proteins that occupy its regulatory elements. The most common method to identify proteins associated with genomic loci is chromatin immunoprecipitation (ChIP). While having greatly advanced our understanding of gene expression regulation, ChIP requires specific, high quality, IP-competent antibodies against nominated proteins, which can limit its utility and scope for discovery. Thus, a method able to discover and identify prot...

https://rxivist.org/papers/11291
https://doi.org/10.1101/159517

13: All-in-One Dual CRISPR-Cas12a (AIOD-CRISPR) Assay: A Case for Rapid, Ultrasensitive and Visual Detection of Novel Coronavirus SARS-CoV-2 and HIV virus

Xiong Ding, Kun Yin et al.

5,868 downloads (posted 21 Mar 2020)

A recent outbreak of novel coronavirus (SARS-CoV-2), the causative agent of COVID-19, has spread rapidly all over the world. Human immunodeficiency virus (HIV) is another deadly virus and causes acquired immunodeficiency syndrome (AIDS). Rapid and early detection of these viruses will facilitate early intervention and reduce disease transmission risk. Here, we present an All-In-One Dual CRISPR-Cas12a (termed "AIOD-CRISPR") assay method for simple, rapid, ultrasensitive, one-pot, and visual detection of coronavirus SARS-...

https://rxivist.org/papers/77429
https://doi.org/10.1101/2020.03.19.998724

14: Platform for rapid nanobody discovery in vitro

Conor McMahon, Alexander S Baier et al.

5,688 downloads (posted 16 Jun 2017)

Camelid single-domain antibody fragments ('nanobodies') provide the remarkable specificity of antibodies within a single immunoglobulin VHH domain. This unique feature enables applications ranging from their use as biochemical tools to therapeutic agents. Virtually all nanobodies reported to date have been obtained by animal immunization, a bottleneck restricting many applications of this technology. To solve this problem, we developed a fully in vitro platform for nanobody discovery based on yeast surface display of a ...

https://rxivist.org/papers/11316
https://doi.org/10.1101/151043

15: Aequorea victoria’s secrets

Talley Lambert, Hadrien Depernet et al.

5,651 downloads (posted 19 Jun 2019)

Using mRNA-Seq and de novo transcriptome assembly, we identified, cloned and characterized nine previously undiscovered fluorescent protein (FP) homologs from Aequorea victoria and a related Aequorea species, with most sequences highly divergent from avGFP. Among these FPs are the brightest GFP homolog yet characterized and a reversibly photochromic FP that responds to UV and blue light. Beyond green emitters, Aequorea species express purple- and blue-pigmented chromoproteins (CPs) with absorbances ranging from green to...

https://rxivist.org/papers/53702
https://doi.org/10.1101/677344

16: Activity profiling and structures of inhibitor-bound SARS-CoV-2-PLpro protease provides a framework for anti-COVID-19 drug design

Wioletta Rut, Zongyang Lv et al.

5,592 downloads (posted 29 Apr 2020)

In December 2019, the first cases of a novel coronavirus infection causing COVID-19 were diagnosed in Wuhan, China. Viral Papain-Like cysteine protease (PLpro, NSP3) is essential for SARS-CoV-2 replication and represents a promising target for the development of antiviral drugs. Here, we used a combinatorial substrate library containing natural and a wide variety of nonproteinogenic amino acids and performed comprehensive activity profiling of SARS-CoV-2-PLpro. On the scaffold of best hits from positional scanning we de...

https://rxivist.org/papers/81671
https://doi.org/10.1101/2020.04.29.068890

17: Thermal Decomposition Of The Amino Acids Glycine, Cysteine, Aspartic Acid, Asparagine, Glutamic Acid, Glutamine, Arginine And Histidine

Ingrid M Weiss, Christina Muth et al.

5,016 downloads (posted 22 Mar 2017)

Calorimetry, thermogravimetry and mass spectrometry were used to follow the thermal decomposition of the eight amino acids G, C, D, N, E, Q, R and H between 185 °C and 280 °C. Endothermic heats of decomposition between 72 and 151 kJ/mol are needed to form 12 to 70 % volatile products. This process is neither melting nor sublimation. With exception of cysteine they emit mainly H2O, some NH3 and no CO2. Cysteine produces CO2 and little else. The reactions are described by polynomials, AA → a (NH3) + b (H2O) + c (CO2) + d ...

https://rxivist.org/papers/11388
https://doi.org/10.1101/119123

18: CRISPR-Cas12a target binding unleashes single-stranded DNase activity

Janice S Chen, Enbo Ma et al.

4,995 downloads (posted 29 Nov 2017)

CRISPR-Cas12a (Cpf1) proteins are RNA-guided DNA targeting enzymes that bind and cut DNA as components of bacterial adaptive immune systems. Like CRISPR-Cas9, Cas12a can be used as a powerful genome editing tool based on its ability to induce genetic changes in cells at sites of double-stranded DNA (dsDNA) cuts. Here we show that RNA-guided DNA binding unleashes robust, non-specific single-stranded DNA (ssDNA) cleavage activity in Cas12a sufficient to completely degrade both linear and circular ssDNA molecules within mi...

https://rxivist.org/papers/11145
https://doi.org/10.1101/226993

19: In silico approach toward the identification of unique peptides from viral protein infection: Application to COVID-19

Ben Orsburn, Conor Jenkins et al.

4,971 downloads (posted 10 Mar 2020)

We describe a method for rapid in silico selection of diagnostic peptides from newly described viral pathogens and applied this approach to SARS-CoV-2/COVID-19. This approach is multi-tiered, beginning with compiling the theoretical protein sequences from genomic derived data. In the case of SARS-CoV-2 we begin with 496 peptides that would be produced by proteolytic digestion of the viral proteins. To eliminate peptides that would cause cross-reactivity and false positives we remove peptides from consideration that have...

https://rxivist.org/papers/76320
https://doi.org/10.1101/2020.03.08.980383

20: Enhanced proofreading governs CRISPR-Cas9 targeting accuracy

Janice S Chen, Yavuz S. Dagdas et al.

4,760 downloads (posted 06 Jul 2017)

The RNA-guided CRISPR-Cas9 nuclease from Streptococcus pyogenes (SpCas9) has been widely repurposed for genome editing. High-fidelity (SpCas9-HF1) and enhanced specificity (eSpCas9(1.1)) variants exhibit substantially reduced off-target cleavage in human cells, but the mechanism of target discrimination and the potential to further improve fidelity were unknown. Using single-molecule Förster resonance energy transfer (smFRET) experiments, we show that both SpCas9-HF1 and eSpCas9(1.1) are trapped in an inactive state whe...

https://rxivist.org/papers/11253
https://doi.org/10.1101/160036