Nanoscale warriors against viral invaders: a comprehensive review of Nanobodies as potential antiviral therapeutics

Abstract

Viral infections remain a significant global health threat, with emerging and reemerging viruses causing epidemics and pandemics. Despite advancements in antiviral therapies, the development of effective treatments is often hindered by challenges, such as viral resistance and the emergence of new strains. In this context, the development of novel therapeutic modalities is essential to combat notorious viruses. While traditional monoclonal antibodies are widely used for the treatment of several diseases, nanobodies derived from heavy chain-only antibodies have emerged as promising "nanoscale warriors" against viral infections. Nanobodies possess unique structural properties that enhance their ability to recognize diverse epitopes. Their small size also imparts properties, such as improved bioavailability, solubility, stability, and proteolytic resistance, making them an ideal class of therapeutics for viral infections. In this review, we discuss the role of nanobodies as antivirals against various viruses. Techniques used for developing nanobodies, delivery strategies are covered, and the challenges and opportunities associated with their use as antiviral therapies are discussed. We also offer insights into the future of nanobody-based antiviral research to support the development of new strategies for managing viral infections.

Keywords: Antiviral; Single-domain antibodies; camelid antibodies; intranasal delivery; nanobodies; phage display; viral infections; virus.

Figure 1.

Comparison of conventional and camelid-derived antibody structures. (a) Conventional IgG antibodies consist of two heavy chains and two light chains. The antigen-binding site is formed by the variable domains of the heavy (VH) and light (VL) chains. (b) Camelid heavy chain-only antibodies (HCAbs) lack the light chain and have a single variable heavy domain (VHH) responsible for antigen binding. (c) The VHH domain of HCAbs is called a nanobody. Sequence differences between VH and VHH at key positions (amino acid 37, 44, 45, 47 as per Kabat numbering system) are shown. (the figure has been made using Microsoft PowerPoint).

Figure 2.

Strategies for production of nanobodies. Target-specific nanobodies can be discovered using (a) phage display-based selection from immunized, naïve, semi-synthetic or synthetic camelid libraries (b) immunization of transgenic mice encoding HCAbs (c) ai/ml-based prediction (d) next-generation sequencing (NGS) of selected phage libraries (e) after selection, VHHs can be produced in prokaryotic or eukaryotic systems for downstream applications (the figure has been made using Microsoft PowerPoint).