Evidence supporting the use of peptides and peptidomimetics as potential SARS-CoV-2 (COVID-19) therapeutics.
Ontology highlight
ABSTRACT:
SUBMITTER: VanPatten S
PROVIDER: S-EPMC7364852 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Over 50 peptides, which were known to inhibit SARS-CoV-1, were computationally screened against the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2. Based on the binding affinity and interaction, 15 peptides were selected, which showed higher affinity compared to the α-helix of the human ACE2 receptor. Molecular dynamics simulation demonstrated that two peptides, S2P25 and S2P26, were the most promising candidates, which could potentially block the entry of SARS-CoV-2. Tyr489 and Tyr505 residues present in the "finger-like" projections of the RBD were found to be critical for peptide interaction. Hydrogen bonding and hydrophobic interactions played important roles in prompting peptide-protein binding and interaction. Structure-activity relationship indicated that peptides containing aromatic (Tyr and Phe), nonpolar (Pro, Gly, Leu, and Ala), and polar (Asn, Gln, and Cys) residues were the most significant contributors. These findings can facilitate the rational design of selective peptide inhibitors targeting the spike protein of SARS-CoV-2.
| S-EPMC7605242 | biostudies-literature
Project description:The SARS-CoV-2 infection triggers host kinases and is responsible for heavy phosphorylation in the host and also in the virus. Notably, phosphorylations in virus were achieved using the host enzyme for its better survival and further mutations. We have attempted to study and understand the changes that happened in phosphorylation during and post SARS-CoV-2 infection. There were about 70 phosphorylation sites detected in SARS-CoV-2 viral proteins including N, M, S, 3a, and 9b. Furthermore, more than 15,000 host phosphorylation sites were observed in SARS-CoV-2-infected cells. SARS-CoV-2 affects several kinases including CMGC, CK2, CDK, PKC, PIKFYVE, and EIF2AK2. Furthermore, SARS-CoV-2 regulates various signaling pathways including MAPK, GFR signaling, TGF-β, autophagy, and AKT. These elevated kinases and signaling pathways can be potential therapeutic targets for anti-COVID-19 drug discovery. Specific inhibitors of these kinases and interconnected signaling proteins have great potential to cure COVID-19 patients and slow down the ongoing COVID-19 pandemic.
| S-EPMC8891488 | biostudies-literature
Project description:Several variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were observed since the outbreak of the global pandemic at the end of 2019. The trimeric spike glycoprotein of the SARS-CoV-2 virus is crucial for the viral access to the host cell by interacting with the human angiotensin converting enzyme 2 (ACE2). Most of the mutations take place in the receptor-binding domain (RBD) of the S1 subunit of the trimeric spike glycoprotein. In this work, we targeted both S1 and S2 subunits of the spike protein in the wild type (WT) and the Omicron variant guided by the interaction of the neutralizing monoclonal antibodies. Virtual screening of two different peptidomimetics databases, ChEMBL and ChemDiv databases, was carried out against both S1 and S2 subunits. The use of these two databases provided diversity and enhanced the chance of finding protein-protein interaction inhibitors (PPIIs). Multi-layered filtration, based on physicochemical properties and docking scores, of nearly 114,000 compounds found in the ChEMBL database and nearly 14,000 compounds in the ChemDiv database was employed. Four peptidomimetics compounds were effective against both the WT and the Omicron S1 subunit with the minimum binding free energy of -25 kcal/mol. Five peptidomimetics compounds were effective against the S2 subunit with the minimum binding free energy of -19 kcal/mol. The dynamical cross-correlation matrix insinuated that the mutations of the RBD in the Omicron variant of the SARS-CoV-2 virus altered the correlated conformational motion of the different regions of the protein.Communicated by Ramaswamy H. Sarma.
| S-EPMC9971351 | biostudies-literature
Project description:SARS-CoV-2 is a positive-sense RNA virus and it is the causative agent of the global COVID-19 outbreak. COVID-19 is similar to the previous outbreaks for instance SARS in 2002-2003 and MERS in 2012. As the peptides have many advantages, peptide-based therapeutics might be one of the possible ways in the development of COVID-19 specific drugs. SARS-CoV-2 enters into a human via its S protein by attaching with human hACE2 present on the cell membrane in the lungs and intestines of humans. hACE2 cleaves S protein into the S1 subunit for viral attachment and the S2 subunit for fusion with the host cell membrane. The fusion mechanism forms a six-helical bundle (6-HB) structure which finally fuses the viral envelope with the host cell membrane. hACE2 based peptides such as SBP1 and Spikeplug have shown their potential as antiviral agents. S protein-hACE2 interaction and the SARS-CoV-2 fusion machinery play a crucial part in human viral infection. It is evident that if these interactions could be blocked successfully and efficiently, it could be the way to find the drug for COVID-19. Several peptide-based inhibitors are potent inhibitors of S protein-hACE2 interaction. Similarly, the antiviral activity of the antimicrobial peptide, lactoferrin makes it an important candidate for the COVID-19 drug development process. A candidate drug, RhACE2-APN01 based on recombinant hACE2 peptide has already entered phase II clinical trials. This review sheds light on different aspects of the feasibility of using peptide-based therapeutics as the promising therapeutic route for COVID-19.
| S-EPMC8498005 | biostudies-literature
Project description:The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is still affecting people worldwide. Despite the good degree of immunological protection achieved through vaccination, there are still severe cases that require effective antivirals. In this sense, two specific pharmaceutical preparations have been marketed already, the RdRp polymerase inhibitor molnupiravir and the main viral protease inhibitor nirmatrelvir (commercialized as Paxlovid, a combination with ritonavir). Nirmatrelvir is a peptidomimetic acting as orally available, covalent, and reversible inhibitor of SARS-CoV-2 main viral protease. The success of this compound has revitalized the search for new peptide and peptidomimetic protease inhibitors. This highlight collects some selected examples among those recently published in the field of SARS-CoV-2.
| S-EPMC9877768 | biostudies-literature
Project description:To date, the current COVID-19 pandemic caused by SARS-CoV-2 has infected 99.2 million while killed 2.2 million people throughout the world and is still spreading widely. The unavailability of potential therapeutics against this virus urges to search and develop new drugs. SARS-CoV-2 enters human cells by interacting with human angiotensin-converting enzyme 2 (ACE2) receptor expressed on human cell surface through utilizing receptor-binding domain (RBD) of its spike glycoprotein. The RBD is highly conserved and is also a potential target for blocking its interaction with human cell surface receptor. We designed short peptides on the basis of our previously reported truncated ACE2 (tACE2) for increasing the binding affinity as well as the binding interaction network with RBD. These peptides can selectively bind to RBD with much higher affinities than the cell surface receptor. Thus, these can block all the binding residues required for binding to cell surface receptor. We used selected amino acid regions (21-40 and 65-75) of ACE2 as scaffold for the de novo peptide design. Our designed peptide Pep1 showed interactions with RBD covering almost all of its binding residues with significantly higher binding affinity (-13.2 kcal mol-1) than the cell surface receptor. The molecular dynamics (MD) simulation results showed that designed peptides form a stabilized complex with RBD. We suggest that blocking the RBD through de novo designed peptides can serve as a potential candidate for COVID-19 treatment after further clinical investigations.
| S-EPMC8430035 | biostudies-literature
Project description:ACE2 on epithelial cells is the SARS-CoV-2 entry receptor. Single-cell RNA-sequencing data derived from two COVID-19 cohorts revealed that MAP4K3/GLK-positive epithelial cells were increased in patients. SARS-CoV-2-induced GLK overexpression in epithelial cells correlated with COVID-19 severity and vesicle secretion. GLK overexpression induced the epithelial cell-derived exosomes containing ACE2; the GLK-induced exosomes transported ACE2 proteins to recipient cells, facilitating pseudovirus infection. Consistently, ACE2 proteins were increased in the serum exosomes from another COVID-19 cohort. Remarkably, SARS-CoV-2 spike protein stimulated GLK, and GLK stabilized ACE2 in epithelial cells. Mechanistically, GLK phosphorylated ACE2 at two serine residues (Ser776, Ser783), leading to dissociation of ACE2 from its E3 ligase UBR4. Reduction of UBR4-induced Lys48-linked ubiquitination at three lysine residues (Lys26, Lys112, Lys114) of ACE2 prevented its degradation. Furthermore, SARS-CoV-2 pseudovirus or live virus infection in humanized ACE2 mice induced GLK and ACE2 protein levels, as well as ACE2-containing exosomes. Collectively, ACE2 stabilization by SARS-CoV-2-induced MAP4K3/GLK may contribute to the pathogenesis of COVID-19.
| S-SCDT-EMM-2022-15904 | biostudies-other
Project description:The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Covid-19 pandemic has caused high morbidity and mortality rates worldwide. Virus entry into cells can be blocked using several strategies, including inhibition of protein-protein interactions (PPIs) between the viral spike glycoprotein and cellular receptors, as well as blocking of spike protein conformational changes that are required for cleavage/activation and fusogenicity. The spike-mediated viral attachment and entry into cells via fusion of the viral envelope with cellular membranes involve PPIs mediated by short peptide fragments exhibiting particular secondary structures. Thus, peptides that can inhibit these PPIs may be used as potential antiviral agents preventing virus entry and spread. This review is focused on peptides and peptidomimetics as PPI modulators and protease inhibitors against SARS-CoV-2.
| S-EPMC8646791 | biostudies-literature
Project description:SARS-CoV-2 has an exonuclease-based proofreader, which removes nucleotide inhibitors such as Remdesivir that are incorporated into the viral RNA during replication, reducing the efficacy of these drugs for treating COVID-19. Combinations of inhibitors of both the viral RNA-dependent RNA polymerase and the exonuclease could overcome this deficiency. Here we report the identification of hepatitis C virus NS5A inhibitors Pibrentasvir and Ombitasvir as SARS-CoV-2 exonuclease inhibitors. In the presence of Pibrentasvir, RNAs terminated with the active forms of the prodrugs Sofosbuvir, Remdesivir, Favipiravir, Molnupiravir and AT-527 were largely protected from excision by the exonuclease, while in the absence of Pibrentasvir, there was rapid excision. Due to its unique structure, Tenofovir-terminated RNA was highly resistant to exonuclease excision even in the absence of Pibrentasvir. Viral cell culture studies also demonstrate significant synergy using this combination strategy. This study supports the use of combination drugs that inhibit both the SARS-CoV-2 polymerase and exonuclease for effective COVID-19 treatment.
| S-EPMC8312893 | biostudies-literature
Project description:The need for proven disease-specific treatments for the novel pandemic coronavirus SARS-CoV-2 necessitates a worldwide search for therapeutic options. Since the SARS-CoV-2 virus shares extensive homology with SARS-CoV and MERS-CoV, effective therapies for SARS-CoV and MERS-CoV may also have therapeutic potential for the current COVID-19 outbreak. To identify therapeutics that might be repositioned for treatment of the SARS-CoV-2 disease COVID-19, we strategically reviewed the literature to identify existing therapeutics with evidence of efficacy for the treatment of the three coronaviruses that cause severe respiratory illness (SARS-CoV, MERS-CoV, and SARS-CoV-2). Mechanistic and in vitro analyses suggest multiple promising therapeutic options with potential for repurposing to treat patients with COVID-19. Therapeutics with particularly high potential efficacy for repurposing include camostat mesylate, remdesivir, favipiravir, tocilizumab, baricitinib, convalescent plasma, and humanized monoclonal antibodies. Camostat mesylate has shown therapeutic potential, likely by preventing viral entry into epithelial cells. In early research, the targeted antivirals remdesivir and favipiravir appear to benefit patients by decreasing viral replication; clinical trials suggest that remdesivir speeds recovery from COVID-19. Tocilizumab and baricitinib appear to improve mortality by preventing a severe cytokine storm. Convalescent plasma and humanized monoclonal antibodies offer passive immunity and decreased recovery time. This review highlights potential therapeutic options that may be repurposed to treat COVID-19 and suggests opportunities for further research.
| S-EPMC7412090 | biostudies-literature