Tag: pandemic

Finding the chink in corona’s armour

Finding the chink in corona’s armour

The COVID-19 pandemic resulted in millions of deaths. Despite an unparalleled collaborative research effort that led to effective vaccines and therapies being produced in record-breaking time, a complete understanding of the structure and lifecycle of the coronavirus known as SARS-CoV-2 is still lacking. Scientists used the biolabs and the SPB/SFX instrument at the European XFEL to study the main protease, or Mpro, of the virus to understand how it protects itself from oxidative damage. The results add key knowledge to our understanding of the workings of SARS-CoV-2 and the field of viral biology.

Between January 2020 and March 2023, over six million people died as a result of the respiratory disease COVID-19, and several hundred million were infected. The disease is caused by SARS-CoV-2, a coronavirus. “Coronaviruses are a group of RNA viruses that cause illnesses and diseases in mammals and birds”, explains European XFEL scientist Richard Bean. “However, despite their significant relevance for global human health, there is still a lot to learn about the structure and function of coronaviruses in general and SARS-CoV-2 in particular.”

In response to the outbreak of the pandemic, scientists and scientific organizations around the globe poured efforts into studying the structure, dynamics, and function of SARS-CoV-2 in search of vaccines and therapies. Due to its central role in the replication cycle of the virus, the main protease – an enzyme that liberates newly made pieces of the virus from one another – soon emerged as a key antiviral drug target. The main protease, or Mpro, is particularly attractive for drug development because it plays a central role in viral replication, and also because it is quite different from all human proteins. This allows therapies to specifically target the virus while minimizing side effects that might harm patients. Previous drug discovery programmes targeting other viruses have succeeded using viral protease inhibitors, making a successful outcome in the case of SARS-CoV-2 more likely. “While the height of the COVID-19 pandemic may have passed, there is still a lot of value in studying the SARS-CoV-2 virus”, enhances Thomas Lane from the Center for Free-Electron Laser Science (CFEL) in Hamburg. “COVID continues to present a significant health threat worldwide. Given the persistence of this virus and the possible emergence of future pathogenic coronaviruses, it is imperative we develop a deeper understanding of Mpro and its role in viral function.”

In a recent experiment at the SPB/SFX instrument at the European XFEL, Lane and colleagues used the intense X-ray beam to study Mpro. Several previous structural studies focusing on Mpro have highlighted a number of peculiarities. “Firstly, the protein forms a 3D structure known as a dimer when it is found in high concentrations”, explains European XFEL scientist Robin Schubert, who was involved in the experiment. “This structural habit seems to directly influence its activity—but we don’t know precisely why this is important for the virus.”

Read more on XFEL website

Image: An understanding of the structure and lifecycle of the SARS-CoV-2 virus is essential to develop vaccines and therapies.

Credit: CFEL

Unique Novel Drug Shows Promise Against SARS-CoV-2

Unique Novel Drug Shows Promise Against SARS-CoV-2

SARS-CoV-2 is an RNA virus that caused a three-year long pandemic with millions of reported deaths worldwide.1,2  Despite the unprecedented speed of development and approval of SARS-CoV-2 vaccines and oral antivirals especially Paxlovid (co-administered Nirmatrelvir with ritonavir), there remain risks for emerging variants of concern (VOCs) with increased virulence and infectivity, and clinical challenges especially for population at risk who cannot benefit from existing drugs due to potential drug-drug interactions (DDIs). Continued development of oral antiviral drugs with improved antiviral potency and safety are needed to address current challenges in clinical practice for treatment of COVID-19.

Olgotrelvir (STI-1558) is designed as a potent standalone antiviral drug with excellent oral bioavailability, limited drug-drug interactions, and antiviral efficacy at doses with low safety concerns.  Olgotrelvir and its parent drug AC1115 potently inhibit activities of SARS-CoV-2 main protease (Mpro) including Mpro mutants found in SARS-CoV-2 VOCs, as well as Mpro mutants such as E166 found to be resistant to Paxlovid. In addition, olgotrelvir inhibits activity of human cathepsin L (CTSL), the major host cysteine protease aiding in virus entry through the endosomal pathway.3-5 The dual inhibition of both virus entry and virus replication pathways may enhance the robustness of the antiviral effect and reduce potential drug resistance. Indeed, olgotrelvir and AC1115 displayed potent antiviral activities against SARS-CoV-2 variants in cell-based models and in humanized transgenic mouse models. In phase 1 clinical trials, orally administered olgotrelvir demonstrated effective plasma exposure, limited mild adverse events, and a positive trend of reducing the SARS-CoV-2 viral RNA copy loads. Considering the favorable efficacy and pharmacokinetic profile along with data supporting the positive safety profile of the compound, olgotrelvir is a promising anti-SARS-CoV-2 drug candidate, which warrants further development as a next-generation therapeutic intervention for COVID-19 and potentially other coronaviruses.

Read more on SLAC website

Image: High resolution of co-crystal structure of SARS-CoV-2 Mpro or human cathepsin L complexed with AC1115. (A) SARS-CoV-2 Mpro (gray surface) bound with AC1115 (pink sticks). Electron density corresponding to AC1115 is shown in pink mesh. Hydrophobic residues of the Mpro catalytic active site binding pocket are labeled; with the active site cysteine shown in yellow. (B) Hydrogen bond interactions between AC1115 and Mpro are denoted with black lines. AC1115 forms 7 direct hydrogen bonds with Mpro residues, with additional polar interactions mediated by water molecules (red spheres). (C) CTSL protein (surface and cartoon) with covalently bound AC1115 (green sticks). Amino acid residues contacting AC1115 are labeled; the catalytic cysteine (Cys25) is additionally indicated by the yellow protein surface. (D) AC1115 hydrogen bonds with CTSL amino acids are shown (red dashed lines), along with the covalent bond to the Cys25 side chain sulfur atom (black line).   The two structures were deposited to PDB with IDs of 8UAB and 8UAC.

Researchers visualise in 3D how SARS-CoV-2 replicates in cells

Researchers visualise in 3D how SARS-CoV-2 replicates in cells

The use of different microscopy and tomography techniques, including synchrotron light, unveils how lung cells are modified along the infection in cell culture models. The work is the result of the European consortium CoCID (Compact Cell Imaging Device) with the participation of CSIC groups and the ALBA Synchrotron.

The covid-19 pandemic has affected more than 770 million people and has caused the death of nearly seven million people around the world. Its huge impact on health and global economy has promoted research in the field since 2020, although it is still necessary to understand how this infection makes progress with the aim of finding specific solutions to this pathogen. Now, a team from the Spanish National Research Council (CSIC) and the ALBA Synchrotron publishes in the journal ACS Nano the results obtained after three-dimensional analysis of the interior of an infected cell.

Members of the National Centre of Biotechnology (CNB-CSIC) and the ALBA Synchrotron, the only synchrotron light source in Spain located in Cerdanyola del Vallès (Barcelona), have imaged in three dimensions the interior of human lung epithelium cells, the primary target of the virus, and the severe structural changes caused by SARS-CoV-2 infection.

Pablo Gastaminza, CNB-CSIC researcher and main author of the work, explains the alterations they found: “when comparing an uninfected cell with an infected one, we can see that the virus multiplication machinery forms vesicles and tubules as well as remarkable signs of stress on cellular organelles such as mitochondria and the endoplasmic reticulum.”

The study is part of the collaboration established within the European CoCID (Compact Cell Imaging Device) consortium. It combines the use of molecular biology, virology and three types of microscopy techniques. One of them is the so-called soft X-ray cryo-tomography (Cryo-SXT), a technology available only in four places all over the world, including the MISTRAL beamline at the ALBA Synchrotron. This technique allows “to generate three-dimensional maps of the ultrastructure of complete cells, reconstructing their total volume and providing extra information to other techniques like electron microscopy,” according to Eva Pereiro, head of the MISTRAL beamline at ALBA.

Read more on ALBA website

Image: Three-dimensional images of a fragment of a control cell (left) and a cell infected with SARS-CoV-2 (right). The cell nucleus is highlighted in purple, healthy mitochondria in green, and mitochondria modified by the infection in red, the vacuoles in light blue, the viral factory in yellow and the viral particles in blue. 

Credit: ALBA Synchrotron/CNB-CSIC