Structure-Guided Development of Bivalent Aptamers Blocking SARS-CoV-2 Infection

Area of Science:

• Biochemistry
• Structural Biology
• Virology

Background:

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a global health threat due to its high infectivity and evolving mutations impacting vaccine efficacy.
• The SARS-CoV-2 spike protein is crucial for viral entry into host cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor.

Purpose of the Study:

• To develop aptamers that inhibit SARS-CoV-2 infection by targeting the spike protein.
• To elucidate the mechanism of aptamer-mediated inhibition using structural biology.
• To create optimized bivalent aptamers with enhanced antiviral activity.

Main Methods:

• Cryogenic electron microscopy (cryo-EM) was used to determine the 3D structures of aptamer/receptor-binding domain (RBD) complexes.
• Aptamers were designed to target distinct regions of the RBD, including the ACE2-binding site and an allosteric site.
• Structure-based design principles were applied to minimize and optimize aptamer sequences.

Main Results:

• Aptamers were developed that effectively block the interaction between the SARS-CoV-2 spike protein RBD and ACE2.
• One aptamer directly inhibited ACE2 binding, while another allosterically modulated RBD.
• A bivalent aptamer, combining two optimized aptamers, demonstrated superior inhibition of SARS-CoV-2 infection compared to individual aptamers.

Conclusions:

• Structure-based aptamer design is a potent strategy for developing effective antiviral agents against SARS-CoV-2.
• Optimized bivalent aptamers offer enhanced therapeutic potential for combating SARS-CoV-2 and other viral infections.