EK1 with dual Q1004E/N1006I mutation: a promising fusion inhibitor for the HR1 domain of SARS-CoV-2.
Ontology highlight
ABSTRACT:
SUBMITTER: Yan F
PROVIDER: S-EPMC8694780 | biostudies-literature | 2022 Apr
REPOSITORIES: biostudies-literature
Publications
EK1 with dual Q1004E/N1006I mutation: a promising fusion inhibitor for the HR1 domain of SARS-CoV-2.
The Journal of infection 20211222 4
Similar Datasets
Project description:Continuously emerging highly pathogenic human coronaviruses (HCoVs) remain a major threat to human health, as illustrated in past SARS-CoV and MERS-CoV outbreaks. The development of a drug with broad-spectrum HCoV inhibitory activity would address this urgent unmet medical need. Although previous studies have suggested that the HR1 of HCoV spike (S) protein is an important target site for inhibition against specific HCoVs, whether this conserved region could serve as a target for the development of broad-spectrum pan-CoV inhibitor remains controversial. Here, we found that peptide OC43-HR2P, derived from the HR2 domain of HCoV-OC43, exhibited broad fusion inhibitory activity against multiple HCoVs. EK1, the optimized form of OC43-HR2P, showed substantially improved pan-CoV fusion inhibitory activity and pharmaceutical properties. Crystal structures indicated that EK1 can form a stable six-helix bundle structure with both short α-HCoV and long β-HCoV HR1s, further supporting the role of HR1 region as a viable pan-CoV target site.
| S-EPMC6457931 | biostudies-literature
Project description:The rapid and global propagation of the novel human coronavirus that causes severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has produced an immediate urgency to discover promising targets for the treatment of this virus. In this paper, we studied the spike protein S2 domain of SARS-CoV-2 as it is the most conserved component and controls the crucial fusion process of SARS-CoV-2 as a target for different databases of small organic compounds. Our in silico methodology, based on pharmacophore modeling, docking simulation and molecular dynamics simulations, was first validated with ADS-J1, a potent small-molecule HIV fusion inhibitor that has already proved effective in binding the HR1 domain and inhibiting the fusion core of SARS-CoV-1. It then focused on finding novel small molecules and new peptides as fusion inhibitors. Our methodology identified several small molecules and peptides as potential inhibitors of the fusion process. Among these, NF 023 hydrate (MolPort-006-822-583) is one of the best-scored compounds. Other compounds of interest are ZINC00097961973, Salvianolic acid, Thalassiolin A and marine_160925_88_2. Two interesting active peptides were also identified: AP00094 (Temporin A) and AVP1227 (GBVA5). The inhibition of the spike protein of SARS-CoV-2 is a valid target to inhibit the virus entry in human cells. The discussed compounds reported in this paper led to encouraging results for future in vitro tests against SARS-CoV-2.
| S-EPMC9456533 | biostudies-literature
Project description:The emerging SARS-CoV-2 variants, commonly with many mutations in S1 subunit of spike (S) protein are weakening the efficacy of the current vaccines and antibody therapeutics. This calls for the variant-proof SARS-CoV-2 vaccines targeting the more conserved regions in S protein. Here, we designed a recombinant subunit vaccine, HR121, targeting the conserved HR1 domain in S2 subunit of S protein. HR121 consisting of HR1-linker1-HR2-linker2-HR1, is conformationally and functionally analogous to the HR1 domain present in the fusion intermediate conformation of S2 subunit. Immunization with HR121 in rabbits and rhesus macaques elicited highly potent cross-neutralizing antibodies against SARS-CoV-2 and its variants, particularly Omicron sublineages. Vaccination with HR121 achieved near-full protections against prototype SARS-CoV-2 infection in hACE2 transgenic mice, Syrian golden hamsters and rhesus macaques, and effective protection against Omicron BA.2 infection in Syrian golden hamsters. This study demonstrates that HR121 is a promising candidate of variant-proof SARS-CoV-2 vaccine with a novel conserved target in the S2 subunit for application against current and future SARS-CoV-2 variants.
| S-EPMC9648449 | biostudies-literature
Project description:The prolonged duration of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has resulted in the continuous emergence of variants of concern (VOC, e.g., Omicron) and variants of interest (VOI, e.g., Lambda). These variants have challenged the protective efficacy of current COVID-19 vaccines, thus calling for the development of novel therapeutics against SARS-CoV-2 and its VOCs. Here, we constructed a novel fusion inhibitor-based recombinant protein, denoted as 5-Helix, consisting of three heptad repeat 1 (HR1) and two heptad repeat 2 (HR2) fragments. The 5-Helix interacted with the HR2 domain of the viral S2 subunit, the most conserved region in spike (S) protein, to block homologous six-helix bundle (6-HB) formation between viral HR1 and HR2 domains and, hence, viral S-mediated cell-cell fusion. The 5-Helix potently inhibited infection by pseudotyped SARS-CoV-2 and its VOCs, including Delta and Omicron variants. The 5-Helix also inhibited infection by authentic SARS-CoV-2 wild-type (nCoV-SH01) strain and its Delta variant. Collectively, our findings suggest that 5-Helix can be further developed as either a therapeutic or prophylactic to treat and prevent infection by SARS-CoV-2 and its variants.
| S-EPMC8955665 | biostudies-literature
Project description:COVID-19 is a respiratory viral disease caused by a new coronavirus called SARS-CoV-2. This disease has spread rapidly worldwide with a high rate of morbidity and mortality. The receptor-binding domain (RBD) of protein spike (S) mediates the attachment of the virus to the host's cellular receptor. The RBD domain constitutes a very attractive target for subunit vaccine development due to its ability to induce a neutralizing antibody response against the virus. With the aim of boosting the immunogenicity of RBD, it was fused to the extracellular domain of CD154, an immune system modulator molecule. To obtain the chimeric protein, stable transduction of HEK-293 was carried out with recombinant lentivirus and polyclonal populations and cell clones were obtained. RBD-CD was purified from culture supernatant and further characterized by several techniques. RBD-CD immunogenicity evaluated in mice and non-human primates (NHP) indicated that recombinant protein was able to induce a specific and high IgG response after two doses. NHP sera also neutralize SARS-CoV-2 infection of Vero E6 cells. RBD-CD could improve the current vaccines against COVID-19, based in the enhancement of the host humoral and cellular response. Further experiments are necessary to confirm the utility of RBD-CD as a prophylactic vaccine and/or booster purpose.
| S-EPMC9228316 | biostudies-literature
Project description:The recent COVID-19 pandemic has impacted nearly the whole world due to its high morbidity and mortality rate. Thus, scientists around the globe are working to find potent drugs and designing an effective vaccine against COVID-19. Phytochemicals from medicinal plants are known to have a long history for the treatment of various pathogens and infections; thus, keeping this in mind, this study was performed to explore the potential of different phytochemicals as candidate inhibitors of the HR1 domain in SARS-CoV-2 spike protein by using computer-aided drug discovery methods. Initially, the pharmacological assessment was performed to study the drug-likeness properties of the phytochemicals for their safe human administration. Suitable compounds were subjected to molecular docking to screen strongly binding phytochemicals with HR1 while the stability of ligand binding was analyzed using molecular dynamics simulations. Quantum computation-based density functional theory (DFT) analysis was constituted to analyze the reactivity of these compounds with the receptor. Through analysis, 108 phytochemicals passed the pharmacological assessment and upon docking of these 108 phytochemicals, 36 were screened passing a threshold of -8.5 kcal/mol. After analyzing stability and reactivity, 5 phytochemicals, i.e., SilybinC, Isopomiferin, Lycopene, SilydianinB, and Silydianin are identified as novel and potent candidates for the inhibition of HR1 domain in SARS-CoV-2 spike protein. Based on these results, it is concluded that these compounds can play an important role in the design and development of a drug against COVID-19, after an exhaustive in vitro and in vivo examination of these compounds, in future.
| S-EPMC8139335 | biostudies-literature
Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 pandemic. Currently, as dangerous mutations emerge, there is an increased demand for specific treatments for SARS-CoV-2 infected patients. The spike glycoprotein on the virus envelope binds to the angiotensin converting enzyme 2 (ACE2) on host cells through its receptor binding domain (RBD) to mediate virus entry. Thus, blocking this interaction may inhibit viral entry and consequently stop infection. Here, we generated fusion proteins composed of the extracellular portions of ACE2 and RBD fused to the Fc portion of human IgG1 (ACE2-Ig and RBD-Ig, respectively). We demonstrate that ACE2-Ig is enzymatically active and that it can be recognized by the SARS-CoV-2 RBD, independently of its enzymatic activity. We further show that RBD-Ig efficiently inhibits in-vivo SARS-CoV-2 infection better than ACE2-Ig. Mechanistically, we show that anti-spike antibody generation, ACE2 enzymatic activity, and ACE2 surface expression were not affected by RBD-Ig. Finally, we show that RBD-Ig is more efficient than ACE2-Ig at neutralizing high virus titers. We thus propose that RBD-Ig physically blocks virus infection by binding to ACE2 and that RBD-Ig should be used for the treatment of SARS-CoV-2-infected patients.
| S-EPMC8722722 | biostudies-literature
Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) undergoes mutations at a high rate and with frequent genetic reassortment (antigenic drift/shift), leading to variability in targets. The receptor-binding domain (RBD) of the spike (S) protein has a major role in the binding of SARS-CoV-2 with human angiotensin-converting enzyme 2 (ACE2). Mutations at the RBD influence the binding interaction at the SARS-CoV-2 S-ACE2 interface and impact viral pathogenicity. Here, we discuss different reported mutations of concern in RBD, physicochemical characteristic changes resulting from mutated amino acids and their effect on binding between the RBD and ACE2. Along with mutation informatics, we highlight recently developed small-molecule inhibitors of RBD and the ACE2 interface. This information provides a rational basis for the design of inhibitors against the multivariant strains of SARS-CoV-2.
| S-EPMC9250815 | biostudies-literature
Project description:SARS-CoV-2 is one of the most infectious viruses ever recorded. Despite a plethora of research over the last several years, the viral life cycle is still not well understood, particularly membrane fusion. This process is initiated by the fusion domain (FD), a highly conserved stretch of amino acids consisting of a fusion peptide (FP) and fusion loop (FL), which in synergy perturbs the target cells' lipid membrane to lower the energetic cost necessary for fusion. In this study, through a mutagenesis-based approach, we have investigated the basic residues within the FD (K825, K835, R847, K854) utilizing an in vitro fusion assay and 19F NMR, validated by traditional 13C 15N techniques. Alanine and charge-conserving mutants revealed every basic residue plays a highly specific role within the mechanism of initiating fusion. Intriguingly, K825A led to increased fusogenecity which was found to be correlated to the number of amino acids within helix one, further implicating the role of this specific helix within the FD's fusion mechanism. This work has found basic residues to be important within the FDs fusion mechanism and highlights K825A, a specific mutation made within the FD of the SARS-CoV-2 spike protein, as requiring further investigation due to its potential to contribute to a more virulent strain of SARS-CoV-2.
| S-EPMC11357847 | biostudies-literature
Project description:SARS-CoV-2 caused dramatic health, social and economic threats to the globe. With this threat, the expectation of future outbreak, and the shortage of anti-viral drugs, scientists were challenged to develop novel antivirals. The objective of this study is to develop novel anti-SARS-CoV-2 compounds with dual activity by targeting valuable less-mutated enzymes. Here, we have mapped the binding affinity of >500,000 compounds for potential activity against SARS-CoV-2 main protease (Mpro), papain protease (PLpro) and human furin protease. The enzyme inhibition activity of most promising hits was screened and tested in vitro on SARS-CoV-2 clinical isolate incubated with Vero cells. Computational modelling and toxicity of the compounds were validated. The results revealed that 16 compounds showed potential binding activity against Mpro, two of them showed binding affinity against PLpro and furin protease. Respectively, compounds 7 and 13 showed inhibition activity against Mpro at IC50 0.45 and 0.11 µM, against PLpro at IC50 0.085 and 0.063 µM, and against furin protease at IC50 0.29 µM. Computational modelling validated the binding affinity against all proteases. Compounds 7 and 13 showed significant inhibition activity against the virus at IC50 0.77 and 0.11 µM, respectively. Both compounds showed no toxicity on mammalian cells. The data obtained indicated that compounds 7 and 13 exhibited potent dual inhibition activity against SARS-CoV-2. The dual activity of both compounds can be of great promise not only during the current pandemic but also for future outbreaks since the compounds' targets are of limited mutation and critical importance to the viral infection.
| S-EPMC8107043 | biostudies-literature