Structure‐ and Interaction‐Based Design of Anti‐SARS‐CoV‐2 Aptamers

Abstract

Aptamer selection against novel infections is a complicated and time-consuming approach. Synergy can be achieved by using computational methods together with experimental procedures. This study aims to develop a reliable methodology for a rational aptamer in silico et vitro design. The new approach combines multiple steps: (1) Molecular design, based on screening in a DNA aptamer library and directed mutagenesis to fit the protein tertiary structure; (2) 3D molecular modeling of the target; (3) Molecular docking of an aptamer with the protein; (4) Molecular dynamics (MD) simulations of the complexes; (5) Quantum-mechanical (QM) evaluation of the interactions between aptamer and target with further analysis; (6) Experimental verification at each cycle for structure and binding affinity by using small-angle X-ray scattering, cytometry, and fluorescence polarization. By using a new iterative design procedure, structure-and interaction-based drug design (SIBDD), a highly specific aptamer to the receptorbinding domain of the SARS-CoV-2 spike protein, was developed and validated. The SIBDD approach enhances speed of the high-affinity aptamers development from scratch, using a target protein structure. The method could be used to improve existing aptamers for stronger binding. This approach brings to an advanced level the development of novel affinity probes, functional nucleic acids. It offers a blueprint for the straightforward design of targeting molecules for new pathogen agents and emerging variants.

How E-, L-, and P-Selectins Bind to sLex and PSGL-1: A Quantification of Critical Residue Interactions

“…The partition analysis (PA), as implemented in GAMESS, allows us to circumvent this “inconvenience” by allowing arbitrary monomer definitions (called segments in PA to differentiate them from fragments). − The FMO method, in its many flavors, was successfully used to gain insight into complex biomolecular systems. − The choice of DFTB in our work is motivated by the availability of PA only in combination with this self-consistent field (SCF) method. Nevertheless, as recent works show, it may be an appropriate tool for our needs. , Unless indicated differently, all data discussed in this work is from PA based on FMO2-DFTB3/PCM/D3­(BJ)/3ob calculations.…”

Aptamers Targeting Membrane Proteins for Sensor and Diagnostic Applications

“…The rapid and ultrasensitive technique has recently gained considerable momentum with regard to the detection of respiratory viruses for the purpose of point-of-care testing, especially after the COVID-19 pandemic. When combined with the specificity and versatility (here, Raman-active labeling) of nucleic acid aptamers, the technique was able to reach low limits of detection (that could challenge the limits of PCR techniques) as shown for SARS-CoV-2 [163,164] as well as the influenza A virus [165,166]. SERS was also applied recently for the sensitive detection of cancer biomarkers, such as carcinoembryonic antigen (CEA) [167].…”

Aptamers Enhance Oncolytic Viruses’ Antitumor Efficacy

“…Aptamers have high specificity, selectivity, and binding affinity for their related targets (metal ions, chemical compounds, proteins, cells, and whole micro-organisms) with the equilibrium dissociation constants (KD) ranging from the nanomolar to picomolar range [ 52 , 53 ]. They can also form multiple three-dimensional (3D) structures, due to which aptamers can match a given protein target [ 54 ]. SELEX (Systematic Evolution of Ligands by EXponential Enrichment) technology can be used to find an aptamer for a target that does not yet have antibodies, or, if the antigen is toxic to the host animal, the aptamer can be created in vitro ( Figure 2 ) [ 55 ].…”