According to a paper by Brazilian researchers published in Nano Today, the spatial arrangement of proteins on the surface of SARS-CoV-2 assures highly efficient interaction with target receptors on human cells (schematic nanoscale representation of the interaction between SARS-CoV-2 and micrometric cilia on nasal epithelial cells; image: CNPEM)
Published on 03/15/2021
By Elton Alisson | Agência FAPESP – Certain structural characteristics that make the novel coronavirus, SARS-CoV-2, highly efficient at interacting with the receptors it targets to infect human cells and cause the disease known as COVID-19 could be copied in designing synthetic nanoparticles to deliver drugs in a tightly controlled manner for treatment of tumors, infections, and inflammations, according to a paper by scientists at the Brazilian Center for Research in Energy and Materials (CNPEM)
“SARS-CoV-2 is a nanoparticle that interacts extremely efficiently with the receptor it targets and can serve as a model for the development of synthetic nanoparticles for specific biological applications,” Mateus Borba Cardoso, a researcher at CNPEM and last author of the paper, told Agência FAPESP.
According to Cardoso, viruses, in general, are natural nanoparticles measuring a few nanometers (one nanometer is a billionth of a meter) that interact precisely and efficiently with the organism’s biological machinery and, thanks to homogeneously distributed structural characteristics, achieve excellent results in terms of cell entry and replication.
In the case of SARS-CoV-2, efficient targeting is one of the factors that have enabled the virus to become highly contagious. It enters the human body mainly via the nose, and from there spreads throughout the respiratory tract. In this region, it encounters the protein ACE2 on the motile cilia of nasal and esophageal epithelial cells, to which it binds to start the infection.
Interaction with micrometric cilia on these epithelial cells is highly advantageous to the virus. Each cilium is 50 times longer than the virus – about 5 micrometers (μm) versus about 100 nanometers (nm) – presenting a large surface area with receptors for viral attachment. Interaction with the virus also prevents the cilia from functioning properly in later stages of the disease: in particular, it inhibits the clearance of mucus that could prevent further viral infection.
“The main trigger of COVID-19 is precisely targeted interaction between SARS-CoV-2 and nasal cell ACE2 receptors, with which its binding affinity is ten times stronger than SARS-CoV’s, even though both viruses share 76% of the spike protein’s genetic sequence,” Cardoso said. The spike protein is the part of the virus that binds to ACE2.
In SARS-CoV-2, spikes are distributed homogeneously on the surface of the virus with well-defined geometry and an average distance of 15 nm between spikes. This symmetrical layout optimizes replication and transforms several weak interactions into a strong binding event, increasing the likelihood of cell entry.
The spike is also surprisingly flexible and can rotate into a number of positions matching those of the cilia. This rotational freedom, not usually found in other coronaviruses, also increases the probability of successful binding.
Upon activation, the spike radically changes shape to expose its receptor-binding domain (RBD) to the ACE2 receptors “with incredible affinity”, as the researchers put it in the paper.
“What we’re proposing is the use of these concepts of specificity and efficiency, which enable SARS-CoV-2 to interact very selectively with human cells, to develop nanoparticles with similar characteristics to those of the virus so that they can bind to receptors in a specific region of a tumor, for example. Chemotherapy drug doses and side-effects could be drastically reduced in this manner,” Cardoso said.
Inspiration for nanomedicine
According to the researchers, one of the challenges faced in any effort to produce synthetic nanoparticles that mimic the characteristics of SARS-CoV-2 is precise control of their surface organization. If designers of nanomaterials are to achieve an organizational level comparable to that of the virus, they must surpass current methods by combining a precise synthetic approach with a surface functionalization strategy that permits the control of average distancing between bioactive groups.
Current nanoparticle functionalization methods do not produce a homogeneous surface such as that of SARS-CoV-2, and this probably hinders specific interaction between active groups and their receptors.
Another significant challenge relates to the fact that biological events are highly selective and typically part of cellular responsiveness, particularly receptor-mediated targeting in which the bioactive group undergoes modifications triggered by the cell to complete the interaction. Receptors must surmount obstacles to interaction and evade recognition by the immune system until they find their targets for cell entry. Lack of targeting efficacy frequently leads to an accumulation of functionalized nanoparticles in unwanted cells and tissues, boosting toxicity-related effects. In short, translating viral targeting efficiency to nanomaterial design must combine surface arrangement and architecture with the rationally designed ability of the nanomaterial to perform on-site modifications of its active groups (proteins) so as to increase the efficiency of receptor-mediated interactions and consequently raise cellular internalization rates.
“Here at CNPEM we’ve been developing a platform for the production of nanoparticles for applications in nanomedicine for more than a decade,” Cardoso said. “Like viruses, our particles are mutating to assure continuous improvement of their efficiency.”
The Nano Today article “Nano-targeting lessons from SARS-CoV-2” (doi: 10.1016/j.nantod.2020.101012) by I. R. S. Ribeiro, R. F. da Silva, C. P. Silveira, F. E. Galdino and M. B. Cardoso can be retrieved from: www.sciencedirect.com/science/article/abs/pii/S174801322030181X.