Allosteric Modulation of Small Molecule Drugs on ACE2 Conformational Change upon Binding to SARS-CoV-2 Spike Protein

2021 ◽  
Author(s):  
Duen-Shian Wang ◽  
Hamed S Hayatshahi ◽  
Vindi M. Jayasinghe-Arachchige ◽  
Jin Liu
Keyword(s):  
Conformational Change ◽  
Small Molecule ◽  
Allosteric Modulation ◽  
Spike Protein ◽  
Small Molecule Drugs

scholarly journals Nanovesicles derived from bispecific CAR-T cells targeting the spike protein of SARS-CoV-2 for treating COVID-19

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Tianchuan Zhu ◽  
Yuchen Xiao ◽  
Xiaojun Meng ◽  
Lantian Tang ◽  
Bin Li ◽  
...  
Keyword(s):  
T Cells ◽  
Small Molecule ◽  
Neutralizing Antibodies ◽  
Antiviral Drugs ◽  
Spike Protein ◽  
Viral Resistance ◽  
Single Chain ◽  
Car T Cells ◽  
Small Molecule Drugs ◽  
Car T

Abstract Background Considering the threat of the COVID-19 pandemic, caused by SARS-CoV-2, there is an urgent need to develop effective treatments. At present, neutralizing antibodies and small-molecule drugs such as remdesivir, the most promising compound to treat this infection, have attracted considerable attention. However, some potential problems need to be concerned including viral resistance to antibody-mediated neutralization caused by selective pressure from a single antibody treatment, the unexpected antibody-dependent enhancement (ADE) effect, and the toxic effect of small-molecule drugs. Results Here, we constructed a type of programmed nanovesicle (NV) derived from bispecific CAR-T cells that express two single-chain fragment variables (scFv), named CR3022 and B38, to target SARS-CoV-2. Nanovesicles that express both CR3022 and B38 (CR3022/B38 NVs) have a stronger ability to neutralize Spike-pseudovirus infectivity than nanovesicles that express either CR3022 or B38 alone. Notably, the co-expression of CR3022 and B38, which target different epitopes of spike protein, could reduce the incidence of viral resistance. Moreover, the lack of Fc fragments on the surface of CR3022/B38 NVs could prevent ADE effects. Furthermore, the specific binding ability to SARS-CoV-2 spike protein and the drug loading capacity of CR3022/B38 NVs can facilitate targeted delivery of remdesiver to 293 T cells overexpressing spike protein. These results suggest that CR3022/B38 NVs have the potential ability to target antiviral drugs to the main site of viral infection, thereby enhancing the antiviral ability by inhibiting intracellular viral replication and reducing adverse drug reactions. Conclusions In summary, we demonstrate that nanovesicles derived from CAR-T cells targeting the spike protein of SARS-COV-2 have the ability to neutralize Spike-pseudotyped virus and target antiviral drugs. This novel therapeutic approach may help to solve the dilemma faced by neutralizing antibodies and small-molecule drugs in the treatment of COVID-19. Graphical Abstract

scholarly journals Targeting ACE2-RBD interaction as a platform for COVID19 therapeutics: Development and drug repurposing screen of an AlphaLISA proximity assay

2020 ◽  
Author(s):  
Quinlin M. Hanson ◽  
Kelli M. Wilson ◽  
Min Shen ◽  
Zina Itkin ◽  
Richard T. Eastman ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Drug Repurposing ◽  
Spike Protein ◽  
Potential Therapeutic Target ◽  
Angiotensin Converting Enzyme 2 ◽  
Host Interaction ◽  
Small Molecule Drugs ◽  
Protein Receptor ◽  
Direct Binding

AbstractThe COVID-19 pandemic, caused by SARS-CoV-2, is a pressing public health emergency garnering rapid response from scientists across the globe. Host cell invasion is initiated through direct binding of the viral spike protein to the host receptor angiotensin-converting enzyme 2 (ACE2). Disrupting the spike-ACE2 interaction is a potential therapeutic target for treating COVID-19. We have developed a proximity-based AlphaLISA assay to measure binding of SARS-CoV-2 spike protein Receptor Binding Domain (RBD) to ACE2. Utilizing this assay platform, a drug-repurposing screen against 3,384 small molecule drugs and pre-clinical compounds was performed, yielding 25 high-quality, small-molecule hits that can be evaluated in cell-based models. This established AlphaLISA RBD-ACE2 platform can facilitate evaluation of biologics or small molecules that can perturb this essential viral-host interaction to further the development of interventions to address the global health pandemic.

scholarly journals Cyclodextrin-Based Supramolecular Complexes of Osteoinductive Agents for Dental Tissue Regeneration

Pharmaceutics ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 136
Author(s):  
Masahiko Terauchi ◽  
Atsushi Tamura ◽  
Yoshinori Arisaka ◽  
Hiroki Masuda ◽  
Tetsuya Yoda ◽  
...  
Keyword(s):  
Growth Factors ◽  
Bone Formation ◽  
Small Molecule ◽  
Tissue Regeneration ◽  
Alveolar Bone ◽  
Inclusion Complexation ◽  
Dental Tissue ◽  
Polyelectrolyte Complexes ◽  
Small Molecule Drugs

Oral tissue regeneration has received growing attention for improving the quality of life of patients. Regeneration of oral tissues such as alveolar bone and widely defected bone has been extensively investigated, including regenerative treatment of oral tissues using therapeutic cells and growth factors. Additionally, small-molecule drugs that promote bone formation have been identified and tested as new regenerative treatment. However, treatments need to progress to realize successful regeneration of oral functions. In this review, we describe recent progress in development of regenerative treatment of oral tissues. In particular, we focus on cyclodextrin (CD)-based pharmaceutics and polyelectrolyte complexation of growth factors to enhance their solubility, stability, and bioactivity. CDs can encapsulate hydrophobic small-molecule drugs into their cavities, resulting in inclusion complexes. The inclusion complexation of osteoinductive small-molecule drugs improves solubility of the drugs in aqueous solutions and increases in vitro osteogenic differentiation efficiency. Additionally, various anionic polymers such as heparin and its mimetic polymers have been developed to improve stability and bioactivity of growth factors. These polymers protect growth factors from deactivation and degradation by complex formation through electrostatic interaction, leading to potentiation of bone formation ability. These approaches using an inclusion complex and polyelectrolyte complexes have great potential in the regeneration of oral tissues.

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