New research published in the bioRxiv* preprint server suggests a small cationic peptide known as crotamine may inhibit the replication and transcription of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Crotamine in the D-enantiomer form successfully inhibited SARS-CoV-2 replication by targeting the C30 Endopeptidase (3CLpro protease).
Crotamine is found in rattlesnake Crotalus durissus terrificus venom and has analgesic, antibacterial, and hemolytic properties. Other drugs, such as Enalapril and Eptifibatide, are based on snake venom and approved by the U.S. Food & Drug Administration.
The advantage of the selected wild type was because of their cell penetration properties, even in D-enantiomer form, high stability and specificity, as well as selectivity against the target 3CL protease was observed,” concluded the research team.
Isolating the peptide and administering it at a low dose may help create a coronavirus disease 2019 (COVID-19) treatment for people with severe illness.
The researchers expressed the SARS-CoV-2 3CLpro_GST fusion protein, needed for viral replication, on E.coli Lemo21 cells and later purified them. The viral protease was exposed to both crotamine and modified peptides with substituted cysteine residues known as L-CDP2-9 to determine the best inhibitor peptide.
First inhibition tests showed that L-CDP1, L-CDP2, L-CDP7, and L-CDP8 peptides had an 80% inhibition against the viral protease. They also tested the minimum concentration needed for crotamine to have a 100% inhibition against the 3CLpro protease. A 100% protease inhibition was achieved at 300 µM.
L-CDP1 caused complete inhibition of SARS-CoV-2 protease activity at 30 µM. A crotamine derivative with an amino acid substitution known as L-peptide-7 caused a 100% inhibition at 60 µM.
Substitutions of cysteine residues, specifically a substitution at position 36, increased L-CDP7’s inhibitory activity.
A fluorescence-based protease assay confirmed the peptide’s conformational shape during inhibition. L-CDP1, L-CDP7, and L-CDP8 peptides were found to be competitive inhibitors.
The results indicate that these peptides interact directly with amino acid residues located in the active site or with amino acids located in the substrate-binding region of the protease, preventing substrate entry to the active site,” explained the researchers.
To protect against degradation in L-enantiomer peptides, the research team created CDP1 and CDP7 in D-enantiomer form. The reasoning was that D peptides are more stable; L-CDP peptides can degrade from hydrolysis by proteases. Because the D-peptides were mirror images of L-peptides, the team predicted that binding affinity and their inhibitory effect should be similar. Results showed D-CDP1 and D-CDP7 are also competitive inhibitors. Though, D-CDP1’s interaction with the SARS-CoV-2 protease is ten times stronger than D-CDP7.
Based on the findings, the team next looked at L-CDP1’s and D-CDP1’s molecular docking efficiency using a web simulation. The simulations showed that amino acid residues of the viral protease interacted with ligand binding, suggesting a potential mode of interaction.
The amino acid residue, His41, appeared to interact with the hydrogen bond of L-CDP1’s Lys31 residues. The remaining amino acid residues are in the substrate-binding region, confirming the interaction is competitive inhibition.
D-CDP1, on the other hand, works by placing the peptide in the substrate-binding region, causing the protease’s active site to be blocked.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
Brigham and Women's Hospital in Boston Massachusetts will soon begin Phase I trials of a nasal vaccine designed to prevent or slow the progression of Alzheimer's disease (AD), a press release said. This is the [...]
Nanocomposites are a class of nanomaterials, where one or more nanostructured materials (organic/inorganic) are incorporated in metal, polymer, or ceramic to obtain a new material with many unique properties. Nanocomposites are applied in various [...]
Pfizer – updated version of vaccine ‘ready in 100 days’ if the new Omicron resistant to its current vaccine
Pfizer said it will be able to manufacture and distribute an updated version of its COVID-19 vaccine within 100 days if the new variant Omicron is found to be resistant to its current vaccine. [...]
UK places South Africa on red travel list over B.1.1.529 variant picked up by scientists in country. What is the new variant and why is it a concern? Scientists have detected a new Covid-19 [...]
The B.1.1.529 variant was first spotted in Botswana and six cases have been found in South Africa. Scientists have said a new Covid variant that carries an “extremely high number” of mutations may drive [...]
Scientists are building a new super-resolution microscope that uses laser light to study the inner workings and behaviours of superbugs to gain new insights into how they cause disease. The microscope will allow scientists [...]
Cells can produce unique electrical signals. These signals can be linked to various cancers, such as the breast, lung, liver, brain, pancreas and prostate cancers, meaning that they can be used as indicators for [...]
Conventional microscopes produce enlarged images of small structures or objects with the help of light. Nanoparticles, however, are so small that they hardly absorb or scatter light and, hence, remain invisible. Optical resonators increase [...]
To grow and spread, cancer cells must evade the immune system. Investigators from Brigham and Women's Hospital and MIT used the power of nanotechnology to discover a new way that cancer can disarm its [...]
The creation of nanoscale computers for use in precision health care has long been a dream of many scientists and health care providers. Now, for the first time, researchers at Penn State have produced [...]
Liposomes may be the unsung heroes of the COVID-19 pandemic. Without the protection of these microscopic vesicles, the delicate strands of messenger RNA (mRNA) that lie at the heart of the Pfizer and Moderna [...]
London: Drugmaker Pfizer has signed a deal with a UN-backed group to allow other manufacturers to make its experimental COVID-19 pill, a move that could make the treatment available to more than half of the [...]