Targeted Agglutination of Corona Virus by Tapered Chiral Nanoparticles

doi:10.21203/rs.3.rs-2501398/v1

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Targeted Agglutination of Corona Virus by Tapered Chiral Nanoparticles

https://doi.org/10.21203/rs.3.rs-2501398/v1

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The emergence of new viral threats, wide applications of viruses in biotechnology and challenges associated with viral contamination necessitate multiple types of virustatic agents. Here, we show that highly biocompatible tapered CuS nanoparticles efficiently agglutinate COVID virus with binding affinity dependent on chirality of surface ligands and particle shape. L-penicillamine-stabilized nanoparticles with left-handed curved apexes display half-maximal inhibitory concentration as low as 0.57 pM for authentic SARS-CoV-2 viruses, which is ca 15 times greater than for antibodies. Exposure to elevated temperatures causes no change in activity or biocompatibility of nanoparticles while completely deactivating antibodies. Testing with mice indicates that the chirality-optimized nanoparticles can serve as analogs of high antiviral molecular weight biologics complementing the current spectrum of virustatic agents. Their thermal and chemical stability simplifies their applications in biomedical and biotechnological processes.

Biological sciences/Biotechnology/Nanobiotechnology/Nanoparticles

Physical sciences/Materials science/Nanoscale materials/Nanoparticles

Rapid development of mRNA vaccines, antibody treatments, and small-molecule drugs collectively contributed to the marked reduction of infection rate and deaths from SARS-CoV-2^1–11. Along with scientific advances in drug delivery and design, the COVID-19 pandemic also highlighted fundamental technological problems that remain to be solved for effective mitigation of viral outbreaks. With respect to biologics, these problems include rapid mutations¹², short shelf life¹³, antibody-dependent infection enhancement¹⁴, and reversible virustatic binding¹⁵. An additional problem is thermal sensitivity, which causes numerous problems both in delivery logistics and host responses. Besides deactivation of antibodies,^{16, 17} thermal decomposition of high molecular weight biopolymers also cause strong and unpredictable immunological side effects observed ¹⁸. Interestingly, similar problems are also encountered in biotechnology where viral contamination of products and viral infections among hosts must be effectively mitigated. Therefore, it would be fundamentally interesting and practically relevant to consider previously underutilized set of chemical structures for development of virustatic and potentially virucidal agents that would be inexpensive, versatile, stable, and accessible.

The generic attractive interactions between inorganic nanoparticles (NPs) and biomolecules are known to result in protein coronas^{19, 20}, a dynamic coating of the biomolecules around the NP surface. Complementarity of the surface chemistry, nanoscale shapes,²¹ and repulsive interactions can also lead to 1:1 complexes between NP and proteins²², supraparticles,²³ and periodic supramolecular assemblies^{24, 25}. NPs are known to replicate some biological functions, for instance, enzymatic catalysis^{26, 27} and cell signaling²⁸. The biomimetic functionalities of NPs also manifest in targeted binding of NPs to capsids of SARS-CoV-2^29–31 and other viruses, which diminishes their ability to bind to and infect host cells^13,32. The strong attractive NP-virus interactions combined with rigidity of NPs can deform proteins in viral capsids³³, thereby inhibiting and/or inactivating viruses³⁴. This ability can be enhanced by purposeful multiparameter design of the NPs to fit the geometry and chemistry³⁵ of the capsid proteins³⁶.

One of the essential components of the COVID virus is the spike protein (S) that received extensive attention because it is responsible for binding the SARS-CoV-2 to the angiotensin converting enzyme-2 (ACE2) receptor in the membranes of host cells³⁷. As a part of a homotrimeric spike assembly of the spike, S has a molecular weight of 195 kDa, a length of 16 nm, and width of 12 nm³⁸. Although some amino acids in SARS-CoV-2 mutants may vary, the overall structure of the spike protein, containing S1 (130 kDa, 6 nm), S2 (65 kDa, 4 nm) subunits and the receptor-binding domain (RBD, 35 kDa, 3 nm), does not change³⁹. RBD belongs to S1 and are located on the top of the spike and interface with ACE2. These segments in S are primarily composed of β-sheets and random coils that form a groove creating a geometrical lock-and-key match for the protruding N-terminal α-helix in ACE2. S2 subunit in S is mainly composed of stiff α-helices⁴⁰ forming the stem of the spike.

Chirality is an essential geometrical and chemical factor for the formation of protein complexes. Besides chirality of amino acids, the strong circular dichroism (CD)⁴¹ of the homotrimeric spike protein and high values of Osipov-Pickup-Dunmur (OPD) chirality measures in the RBD segment interfacing with ACE2 (Supplementary Fig. 1) indicate that both molecular and nanoscale chirality of NPs can be significant in targeting SARS-CoV-2 virus. Based on the prior studies showing effects of NP chirality on the affinity of to biomolecules^42–46 in protein coronas¹⁹ and cell membranes,²⁸ we designed tapered chiral NPs to agglutinate SARS-CoV-2 virus.

Tapered CuS Nanoparticles with Multiscale Chirality

We employed CuS NPs of tapered shape with a length of 30 ± 3 nm and base diameter of 10 ± 1 nm (Supplementary Figs. 2–3) because the apexes of these particles with diameters of 2.5 ± 0.2 nm are comparable in dimension and geometry to the typical grooves, pockets, and trenches in protein assemblies³⁶. The hydrophobic-to-hydrophilic ligand exchange following the standard synthesis⁴⁷ resulted in chirality in multiple scales that includes angstrom scale chirality of L/D enantiomeric excess on CuS surface and the nanoscale curved geometry of the NP apex (Figs. 1A-C, Supplementary Figs. 2–3). Chiral, tapered CuS NPs carrying penicillamine (Pen) were denoted as D-NPs, L-NPs, and rac-NPs when D-, L-, and rac-Pen were used as surface ligands, respectively.

The total number of Pen ligands on the surface of the L-NPs was approximately 3200 as determined by liquid chromatography-mass spectrometry (LC-MS) (Supplementary Fig. 3). The Pen layer imparts the overall negative charge to the particles The L-, D-, and rac-NPs displayed zeta potentials of -7.9 ± 0.4 mV, -8.1 ± 0.5 mV, and − 17.9 ± 0.12 mV at physiological pH 7.4, respectively (Supplementary Fig. 3 and Supplementary Table 1) while the S and RBD display zeta potentials of -59.94 ± 1.45 mV and 2.60 ± 0.09 mV, respectively, indicating the possibility of an electrostatically controlled complex between CuS NPs and RBD under biological conditions. The CD spectra of the D-NPs and L-NPs showed broad range optical activity from 300 nm to 1000 nm with intense peaks at 423 nm (28 ± 2 mdeg), 630 nm (118 ± 4 mdeg), and a wide peak at 877 nm (Fig. 1D). Optical asymmetry parameter, that is, g-factor displayed values of 0.03 ± 0.002 at both 950 nm and 620 nm (Fig. 1E).

NPs carrying other ligands, such as citric acid, L-malic acid, L-tartaric acid, and L-glutathione (GSH) displayed markedly different and typically smaller optical activity than Pen-coated NPs (Supplementary Fig. 4), which prompted us to better understand how the molecular scale of Pen’s chirality gives rise to the optical bands in the red and near-infrared parts of the spectrum associated with nanoscale chirality of CuS. The crystal lattice fringes observed in TEM images of Pen-coated NPs exhibited a spacing of 0.281 nm. It corresponds to a (103) plane of the hexagonal crystal lattice (Supplementary Fig. 2, Supplementary Fig. 5), which was consistent with X-ray diffraction (XRD, Fig. 1F) and X-ray photoelectron spectroscopy data (XPS, Supplementary Fig. 6). We reconstructed the overall geometry and unit cell structure for different Pen-functionalized NPs from the TEM images using a Gaussian mixture model and integration classification likelihood criterion⁴⁸. (Figs. 1G-J, Supplementary Fig. 7). We found that the approximately five nm apex in a L-Pen NP is offset from the center line by ~ 1 nm and the tapered section is twisted in the counter-clockwise and clockwise direction for L-NPs and D-NPs, respectively, while remaining untwisted in rac-NPs and ligand-free NPs (Figs. 1K-N, Video file 1). The dislocation maps (Supplementary Fig. 8) show that the twist emerges from the relaxation of the lattice stress accumulated during the nucleation and growth in the hydrophobic medium of 1-dodecanethiol (1-DDT) and trioctylphosphine oxide (TOPO). The curl deformation of the apex occurs via sliding of atomic planes and is facilitated by the ligand exchange (Fig. 1O, Supplementary Fig. 8). Since CD spectra are quite different (Supplementary Fig. 4) and apex twists were not observed for other surface ligands (Supplementary Fig. 4), annealing of dislocations is directly related to the chemistry of surface ligand binding. ¹H NMR, Raman, and FTIR data (Supplementary Fig. 9) indicate that for Pen ligands, both amino acid residues bonded with the NP surface via a strong S-Cu covalent bond, S–H–O hydrogen bonds, and ionic bonds between COO⁻ and Cu²⁺ ions on the NP surface.

Interactions of Chiral NPs and Viral Proteins

To assess the interactions between the L-, D-, and rac-CuS NPs and proteins on the viral surface, we used the entire S protein, subunit S1, and recombinant RBD. Due to strong attractive interactions overcoming electrostatic repulsion, we found that S incubated with L-NPs for two hours formed supraparticles (SPs, Fig. 2A), where L-NPs acquire a predominantly radial orientation with the tip pointed inward (Figs. 2A and 2C, Supplementary Fig. 10). When S was exposed to D-NPs for two hours, SPs also formed, however, the D-NPs acquired a predominantly lateral orientation (Figs. 2D, 2F and Supplementary Fig. 10). Cryo-electron tomography (cryo-ET) afforded a vividly visualization of the difference in organization of the SPs with NPs of different chirality. When L-Pen used as the surface ligands, a tightly interconnected network of the tapered chiral NPs and S was observed (Fig. 2B, 2E and Supplementary Fig. 10). The ability of L-NPs and D-NPs to form SPs is analogous to agglutination of proteins by biomacromolecules via multivalent target-ligand interactions¹³. For example, the average number of S proteins that bind to a single L-NP is 4.3 ± 0.3.

Similar to the spike protein S, its subunits S1 and RBD also formed SPs with both L- and D-NPs (Supplementary Fig. 11). However, no SPs appeared when rac-NPs were incubated with RBD, S1, or S. As the ratio of L-Pen to D-Pen increased, the tendency to form SPs increased, and so did their multivalence. (Supplementary Fig. 12). No agglomeration leading to SPs or other assemblies were observed without proteins, nucleocapsid protein of SARS-CoV-2 (70 kDa, 5 nm), BSA or HSA, (Supplementary Fig. 13) indicating specificity of binding.

The CD spectra of the SPs showed a 70 nm red shift for 700 nm compared to the parent NPs (Figs. 2G-I). L-NPs exhibited a larger red shift than D-NPs, in the presence of the three proteins with the maximum red shift of 77 nm being observed when L-NPs interacted with S (Fig. 2G). SAXS data showed that L-NPs, D-NPs, and rac-NPs exhibited different q values after interacting with spike proteins (Fig. 2J). The Raman scattering spectrum was enhanced by L-NPs interacting with three proteins to a greater extent than with D-NPs indicated strong interaction with the L-NPs, while rac-NPs had almost no enhancement for the Raman signal of three proteins (Supplementary Fig. 14). XPS data for SPs produced by L- and D-NPs further confirmed that L-NPs interact with S stronger than D-NPs as evidenced by the binding energy of N and O atoms shifting to lower values, which indicated the presence of N-Cu and O-Cu coordination bonds in the SPs (Supplementary Fig. 14). Furthermore, the process of SP formation was monitored using DLS, zeta-potential and TEM as a function of time, confirming higher efficacy of agglutination of S by L-NPs (Supplementary Fig. 15).

The binding of the NPs to different viral proteins was also evaluated using ELISA assay and flow cytometry after NP binding to HEK293 cells expressing viral proteins in their membranes (Supplementary Fig. 16). We found that the binding affinity of L-NPs to these three proteins in vitro and in cells are nearly the same. (Table 1 and Supplementary Figs. 17–18). The binding affinity between D-NPs and the three proteins followed the same trend but the values were considerably smaller than for L-NPs (Table 1 and Supplementary Figs. 17–18). The rac-NPs display even lower affinity to the three viral proteins (Fig. 2K, Table 1, and Supplementary Figs. 17–18). Compared with L-NPs, D-NPs and rac-NPs showed approximately 10-fold and 10⁴-fold reduced affinity for the three viral proteins (Table 1), respectively. Confocal images of L- and D-NPs binding three viral proteins in cells also confirmed the higher affinity of L-NPs than D-NPs to viral proteins (Supplementary Fig. 19). As the ratio of L-Pen or D-Pen increased in the coating of the NPs, the affinity between chiral NPs and viral proteins also increased (Fig. 2L). Importantly, the viability of the cells remained high, even at high NP concentrations (Supplementary Fig. 20).

Table 1

The IC₅₀ values of chiral NPs to three viral proteins in PBS and HEK293 cells, respectively.
Groups	IC₅₀ Value		Affinity Constant (K_a)
Groups	PBS	Cells	Affinity Constant (K_a)
L-NPs to S	0.51 (pM)	1.09 (pM)	(5.31 ± 0.28) × 10⁸
L-NPs to S1	1.28 (pM)	2.87 (pM)	(8.66 ± 0.41) × 10⁷
L-NPs to RBD	0.66 (pM)	1.83 (pM)	(2.35 ± 0.12) × 10⁸
D-NPs to S	5.29 (pM)	12.04 (pM)	(5.22 ± 0.26) × 10⁷
D-NPs to S1	14.33 (pM)	31.26 (pM)	(2.02 ± 0.11) × 10⁷
D-NPs to RBD	6.91 (pM)	21.63 (pM)	(2.33 ± 0.12) × 10⁷
rac-NPs to S	16.92 (pM)	17.51 (nM)	(3.16 ± 0.16) × 10⁴
rac-NPs to S1	87.02 (pM)	95.95 (nM)	(9.16 ± 0.48) × 10⁵
rac-NPs to RBD	48.27 (pM)	52.16 (nM)	(6.52 ± 0.29) × 10⁴

Tapered NPs with several other chiral and achiral ligands (Supplementary Fig. 4), such as glutathione (GSH), citric acid (Cit), tartaric acid (TA), and malic acid (MA), were also tested with S. Their IC₅₀ values of 11.2 nM, 17.5 nM, 27.1 nM, and 8.8 nM, were about four orders of magnitude lower than those for L-NPs (Supplementary Fig. 21). No SPs were observed for these NPs with S, even after six hours of incubation (Supplementary Fig. 21). We also tested L-Pen functionalized NPs with different geometrical shapes and related chemistries, such as 8 nm and 20 nm nanospheres of CuS, 40 nm long CuS nanorods, and 3 nm Cu_1.94S nanospheres (Supplementary Fig. 22). Their IC₅₀ values for S were 15.5 nM, 4.5 nM, 12.62 nM, and 13.81 nM, respectively, which is again multiple orders of magnitude smaller than for L-NPs (Supplementary Fig. 23). Other nanomaterials with different morphologies and functionalized with L-Pen, such as ZnO NPs and Au NPs, showed limited affinity to RBD with IC₅₀ values of 9.2 mM and 10.8 µM, respectively. Again, no SPs were formed, indicating the weak attractive interactions between them is associated with the lack of geometrical match (Supplementary Fig. 24). Finally, L-Pen modified SiO₂ NPs showed no affinity to RBD even at very high concentrations (Supplementary Fig. 24, Supplementary Table 1).

The difference in NP affinity is directly related to the thermodynamics of their interactions. Isothermal titration calorimetry (ITC) revealed that the affinity constants, Ka, for the binding of L-NPs to S, S1 subunit, and RBD were (5.31 ± 0.28) × 10⁸, (8.66 ± 0.41) × 10⁷, and (2.35 ± 0.12) × 10⁸, respectively. K_a for the D-NPs binding to the same three viral components were (5.22 ± 0.26) × 10⁷, (2.02 ± 0.11) × 10⁷, and (2.33 ± 0.12) × 10⁷, respectively (Figs. 3A–C, Supplementary Fig. 25). Note that K_a values for both L-NPs and D-NPs with S were more than two times higher than that for S1 and RBD. In parallel with the IC₅₀ values, K_a values for rac-NPs were much lower than for L- or D-NPs: S - K_a = (3.16 ± 0.16) × 10⁴, S1 - K_a = (9.16 ± 0.48) × 10⁵, RBD - K_a = (6.52 ± 0.29) × 10⁴ (Table 1).

Computational Models for NP-Protein Interactions

Comparing quantitative and qualitative characteristics for binding between NPs and the viral proteins presented above, we conclude that geometrical and chiral complementarity between NP apex and RBD leads to high affinity between NPs and spike proteins of the SARS-COV-2 virus. This point can be substantiated by atomistic molecular dynamics (MD) simulations representing the essential twisted spike of the virus (Figs. 3D-I, Supplementary Fig. 26). We observed that after 1 µs of MD simulation, only the L-NP remained with the tip interacting with RBD (Figs. 3D, 3G), while both the D-NP and the rac-NP changed their relative orientation with respect to RBD, interacting laterally instead of through the tip (Figs. 3E-I). Such preferential orientation is consistent with the experimentally observed patterns of aggregation for the SPs with radial and lateral placement of the NPs (Figs. 2A, 2D). Furthermore, based on the analysis of trajectories after energetic/structural relaxation (obtained between 150–1000 ns of simulation time (Supplementary Fig. 27), one L-NP can bind 1.9 RBDs, one D-NP can bind 0.17 RBDs and one rac-NP can bind 0.0006 RBDs, we can estimate that their interaction energies with RBD should be − 1223.6 kJ/mol, − 125.3 kJ/mol, and 0.005 kJ/mol, respectively, which accurately reflects the IC₅₀ and K_a values in Table 1.

Inhibition of Binding of Viral Proteins to ACE2 by Chiral NPs in Vitro

The strong enantiomer-dependent interactions between RBR and NPs prompted us to incubate L-, D-, and rac-NPs with pseudo-type SARS-CoV-2 (in 10 mM PBS buffer) for times ranging from 0 to 2 hours. TEM images showed different stages of agglutination that, in the case of L-NPs, led to complete coverage of virus by NPs after two hours and complete destruction of the envelope proteins as indicated by negative staining TEM imaging (Supplementary Fig. 28). D-NPs and rac-NPs displayed lower and negligible association with this virus, respectively (Supplementary Fig. 28).

The binding between L-NPs and protein components of SARS-CoV2 is strong (Supplementary Table 1). However, one needs to make sure that the formation of the NP-protein indeed inhibits the binding between them and angiotensin-converting enzyme 2 (ACE2) on the surface of mammalian cells. We first investigated whether chiral NPs affect the binding between viral proteins and ACE2 receptors in vitro by ELISA. L-NPs effectively inhibit the binding of viral proteins to ACE2 with IC₅₀ values between 0.52 pM and 2.06 pM for all three proteins. (Supplementary Figs. 29–31, Supplementary Table 2). The inhibitory effect of L-NPs was more than 10 times higher than that of D-NPs. For example, D-NPs inhibit the binding of S protein to ACE2 with an IC₅₀ = 5.72 pM, while L-NPs do the same with an IC₅₀ = 0.52 pM. Rac-NPs also inhibit binding between viral proteins and ACE2, but only at much higher concentrations than D-NPs, as exemplified by IC₅₀ values of 32.29 nM for inhibiting the binding of S to ACE2 (Supplementary Figs. 29–31, Supplementary Table 2).

The role of chirality in binding can be further substantiated by the CD spectra that were convenient for the characterization of the change in configuration when the three viral proteins bind to ACE2. The CD peaks from ACE2 located at 209 nm and 223 nm associated with its α-helixes, decreased in intensity and red-shifted after binding with RBD. Importantly, the CD spectrum of ACE2 recovered to its original state when L-NPs were added (Supplementary Fig. 32), which showed the higher affinity between chiral NPs and viral proteins than that of ACE2 to viral proteins. CD spectra indicate great changes for RBD, S1, and S when they interact with chiral NPs, further substantiating the significance of NP chirality. At the same time, the CD spectra of viral proteins were almost unchanged after interaction with rac-NPs (Supplementary Fig. 32).

To further confirm that the binding between the three viral proteins and ACE2 was blocked by chiral NPs, we labeled the RBD with fluorescein isothiocyanate (FITC-RBD) and ACE2 with Cy3 (Cy3-ACE2). Testing fluorescence resonance energy transfer (FRET) of the NP-protein complexes, FITC-RBD were mixed with Cy3-ACE2 at 37°C for two hours, and the FITC fluorescence decreased significantly and the Cy3 signal was observed under FITC excitation wavelengths due to the binding between RBD and ACE2. The FITC fluorescence recovered however, and no Cy3 signal was seen when the chiral NPs were added into the solution containing the RBD and ACE2 complex. These results indicate that the chiral NPs block the binding between viral proteins and ACE2 (Supplementary Fig. 33).

Chiral NPs Inhibit SARS-CoV-2 in Living Cells

SARS-CoV-2 pseudoviruses, vesicular stomatitis virus G (VSVG), and spike protein S were used to assess chirality-optimized NPs ability to inhibit the attachment of pseudovirus to the ACE2 receptor on BEAS-2B lung cells. The confocal microscopy images showed bright green fluorescence from GFP and white fluorescence from chiral NPs when the SARS-CoV-2 pseudovirus and chiral NPs formed complex (Supplementary Figs. 34–35). Three complementary protocols denoted as Treatments 1, 2, and 3 describing both pre-exposure prophylactic and post-infection medication were implemented. Specifically: Treatment 1 - the pseudovirus was initially incubated with different concentrations of L-NPs for two hours and then added to BEAS-2B cells (Human Bronchial Epithelioid Cells) for 24 hours; Treatment 2 - mixtures of pseudovirus and L-NPs in different concentrations were added to BEAS-2B cells for 24 hours; Treatment 3 - the pseudovirus was initially incubated with BEAS-2B cells for 12 hours and then different concentrations of L-NPs were added into the cells for an additional 12 hours.

As the dose of chiral NPs increased from 0 to 5 pM, their white fluorescence gradually increased. Simultaneously, the green fluorescence of the pseudoviruses gradually disappeared in all three treatments (Figs. 4A–C), indicating that the chiral NPs inhibit the infection. IC₅₀ values of 0.66, 0.79, and 1.02 pM were found for Treatment 1, 2, and 3, respectively (Figs. 4D–4F, Supplementary Fig. 36). D-NPs and rac-NPs revealed 10 and 10⁵ times higher IC₅₀ values than L-NPs, respectively (Supplementary Fig. 36). As a benchmark test for the role of chirality, NPs made with a mixture L-Pen or D-Pen showed a tendency for lower IC₅₀ values as the Pen L/D ratio increased (Fig. 4G, Supplementary Fig. 37). Remarkably, the IC₅₀ value of chiral NPs inhibiting SARS-CoV-2 pseudovirus infected cells is about 15 times lower than that of commercial antibody from Biodragon, China (Supplementary Fig. 38). Chiral NPs and achiral NPs were tested for their ability to inhibit authentic SARS-CoV-2. IC₅₀ values of 0.57 pM, 8.31 pM, and 2.16 nM were found for L-NPs, D-NPs, and rac-NPs, respectively, using cell viability assays (Fig. 4I). Importantly, NPs also showed high stability at high temperatures compared with antibodies, a reflection of the inorganic nature of the particles (Fig. 4H).

L- NPs Accelerate the Clearance of SARS-CoV-2 Pseudovirus in Transgenic Mice

ACE2 is highly expressed in lung epithelial cells targeted by SARS-CoV-2. Following the current practices of treatment and prevention of respiratory diseases, L-NPs were tested as a component of inhalation treatment of mice through a commercial nebulizer. We found that the fluorescence signal derived from the chiral NPs was detected for up to 72 hours, suggesting a resident protection function of NPs in lungs (Supplementary Figs. 39–40), which was also confirmed by ICP-MS analysis of lung tissue (Supplementary Fig. 40). To better assess both prophylactic and treatment options for the chiral NPs, transgenic hACE2 mice expressing the human ACE2 gene were used along with GFP-SARS-CoV-2 pseudovirus (Fig. 5A). In the prophylaxis group, the hACE2 mice resisted SARS-CoV-2 infections, after inhaling the chiral NPs for up to three days when compared with the control group exposed to no virus. In the treatment group, 95% of the pseudovirus in the lung were cleared after treatment with chiral NPs (Figs. 5B–5C). Mouse serological indicators and hematoxylin and eosin (H&E) staining showed that the L-NPs had high biocompatibility with mammalian cells with no observed toxicity⁴⁹ for concentrations specific to high antiviral activity (Fig. 5D–5H, Supplementary Fig. 40). The NPs were stored at temperatures up to 60°C and retained the ability to agglutinate viral proteins (Supplementary Fig. 13), indicating temperature tolerance hardly achievable for high molecular weight biologics exemplified by antibodies.

Chirality-optimized NPs with complex twisted shapes can serve as effective inhibitors of SARS-CoV-2 viruses due to strong specific binding to spike proteins in their capsids. Efficient agglutination of viruses into easy-to-separate supraparticles by inexpensive chiral NPs and their thermal stability simplifies their applications initially, perhaps to mitigate the pandemics in non-human hosts. Importance of virustatic agents with unique combination pf properties pertinent to inorganic NPs is also expected to open new venues for their applications in biotechnology.

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Synthesis of D-NPs, L- NPs, rac-NPs, Cit-NPs, GSH-NPs, MA-NPs and TA-NPs. The syntheses of D-NPs, L-NPs, and rac (racemic)-NPs were carried out by a modified version of the previously published method⁴⁷. CuS NPs were synthesized by heating a mixture of Cu(Ac)₂ (0.2 g) and 1-DDT (50 mL) to 200 ℃ in TOPO (1.74 g) under N₂atmosphere. After 4 h, oil-soluble NPs were purified by centrifugation with the addition of CHCl₃and recoveredthree timesand then resuspended in CHCl_3.Then, water-soluble NPs were obtained by adding a surface ligand solution (100 mg/mL in a mixed solvent consisting of ultrapure water and ethylene glycol) followed by ultrasonication for 2 h.

Pen ligands were purified using recrystallization. Specifically, two enantiomers of penicillamine were fully dissolved in a minimal amount of 0.1 M HCl. Then the solutions of the enantiomers were quickly transferred into a 4 °C water bath for crystallization. This procedure was repeated three times.

The production of the L-NPs involved adding L-Pen solution into the NPs resuspended in CHCl_3.Similarly, D-NPs were produced by adding D-Pen solution into the NPs resuspended in CHCl₃. Rac-NPs were produced by equal amounts of D-Pen and L-Pen being added into the NPs resuspended in CHCl₃. Cit-NPs were produced by adding sodium citrate solution (100 mg/mL) into the NPs resuspended in CHCl₃. GSH-NPs were produced by adding GSH solution (25 mg/mL) into the NPs resuspended in CHCl₃. MA-NPs were produced by adding malic acid solution (100 mg/mL) into the NPs resuspended in CHCl₃. Finally, TA-NPs were produced by adding tartaric acid solution (100 mg/mL) into the NPs resuspended in CHCl₃.

Synthesis of 8 nm CuS NPs with Pen as surface ligands. The 8 nm CuS NPs were synthesized by heating 1-DDT solution and Cu(Ac)₂ under a N₂atmosphere⁵⁰. Typically, Cu(Ac)₂ (0.13 g) was dispensed into 30 mL of 1-DDT under magnetic stirring in the presence of N₂ gas and then heated for 20 min to 200 °C. Oil-soluble NPs were purified by centrifugation with the addition of CHCl₃ and recovered three-timesand resuspended in CHCl_3.Then water-soluble NPs were obtained by adding ligand solution (100 mg/mL) with ultrasonic treatment for 2 h. The L-CuS NPs (8 nm) were produced by adding L-Pen solution into the above-mentioned NPs that were resuspended in CHCl₃ and the D-CuS NPs (8 nm) were produced by adding D-Pen solution into the above-mentioned NPs that were resuspended in CHCl_3.

Synthesis of 25 nm CuS NPs with Pen as surface ligands. The 25 nm CuS NPs were synthesized by heating 1-DDT solution and Cu(Ac)₂ under a N₂atmosphere⁵¹. Typically, of Cu(Ac)₂ (0.13 g) was dispersed in 30 mL of 1-DDT under magnetic stirring in the presence of nitrogen gas and then heated to 200°C for 60 min. Oil-soluble NPs were purified by centrifugation with the addition of CHCl₃ three-timesand then resuspended in CHCl_3.The water-soluble NPs were obtained by adding ligand solution (100 mg/mL) with ultrasonic treatment for 2 h. The L-CuS NPs (25 nm) were produced by adding L-Pen solution into the above-mentioned NPs that were resuspended in CHCl₃and D-CuS, and NPs (25 nm) were produced by adding D-Pen solution into the above-mentioned NPs that were resuspended in CHCl_3.

Synthesis of Cu_1.94S Nanospheres with Pen as surface ligands. The spherical Cu_1.94S NPs with a diameter of 3 nm with Pen as surface ligand were synthesized according to previously reported methods with brief modifications⁵⁰. 1-DDT (4.5 mL) and ethanol (10 mL) were mixed in a glass vial and a separate solution containing 1.1 g of Cu(NO₃)₂·3H₂O and 5 mL of H₂O was produced. The two solutions were mixed and vigorously stirred to form a yellow-white suspension. The suspension was collected by centrifugation, washed two times with H₂O and ethanol (volume ratio of 1:2) to remove the excess reagents, and then dried in a vacuum desiccator overnight to purification. A yellow-white powder was obtained by drying in a 60 ℃ vacuum dryer for 1 week, and 20 mg of powder was placed in a glass vial and heated for 30 min to 200 °C. The dark-brown liquid was collected and dispersed in CHCl₃. Purified nanodots were obtained by centrifuging at 10000 rpm for 20 min. This purification process was repeated three times. Then water-soluble NPs were obtained by addition of a Pen solution (100 mg/mL) and ultrasonic treatment for 2 h at pH 9.

Synthesis of CuS nanorods with Pen as surface ligands. The CuS nanorods (NRs) with a length of 45 nm and diameter of 4 nm with Pen as the surface ligand were synthesized according to previously reported methods with small modifications⁵². Copper acetate (0.4 g) was dissolved in 1-octadecene (10 mL) and TOPO (4 g) was added. The reaction was stirred at room temperature for 30 min under a N₂atmosphere. Then, the mixture was heated to 180 ℃. At this point, tert-DDT (7.5 mL) was injected, and the reaction was allowed to proceed for 10 min. The resulting product was then cooled to room temperature, washed several times with ethanol, and redissolved in CHCl₃. Then, water-soluble NRs were obtained by the addition of Pen solution (100 mg/mL) followed by ultrasonic treatment for 2 h in the presence of SDS (10 mM).

Synthesis of SiO₂ Nanospheres with Pen as the surface ligands. The spherical SiO₂ NPs with Pen as surface ligand were synthesized according to previous methods with brief modifications⁵³. L-Pen (15 mg) was dissolved into 4 mL H₂O and after stirring for 5 min, ethanol (4 mL) was added for another 5 min under stirring. TEOS (1 mL) and ammonia solution (100 μL) were added into the above solution and then the mixture was heated for 20 min at 60 °C. Finally, this reaction was left at room temperature for 10 h and the purified L-Pen modified SiO₂ NPs were centrifuged (3000 rpm for 10 min).

Synthesis of ZnO pyramids with Pen as surface ligands. The ZnO pyramids with Pen as the surface ligands were synthesized according to previous methods with brief modifications⁵⁴. In a typical synthesis, C₄H₆O₄Zn·2H₂O (100 mg) and KOH (20 mg) were added into 1 mL of isopropyl alcohol, 4 mL H₂O and L-Pen (15 mg) in a 20 mL round-bottom flask. The mixture was then magnetically stirred for 72 h at room temperature and the white precipitates were separated by centrifugation (7000 rpm 10 min).

Synthesis of spherical Au NPs with Pen as surface ligands. The spherical Au NPs with Pen as surface ligands were synthesized according to previous methods with brief modifications^{55, 56}. In a typical synthesis, L-Pen (7.5 mg) was added to a 20 mL three-necked flask containing 10 mL H₂O and 60 mg of HAuCl₄·3H₂O under vigorous stirring for 2 min at room temperature and then quickly transferred to an oil bath (95 ℃) and heated for 30 min. After the heated solution cooled to room temperature it was placed in a refrigerator to mature for 72 h. Then, 200 μL of the above-mentioned matured solution and 3 mL of H₂O were added into a 10 mL three-necked flask containing sodium borohydride (1.89 mg), trisodium citrate (14.7 mg), L-Pen (15 mg) and stirred vigorously for 2 h. Finally, the precipitates were separated by centrifugation (9000 rpm 10 min).

TEM imaging for chiral CuS NPs. NPs were drop cast for TEM measurements on TEM grids (ultrathin carbon film on holey carbon support film, 200 mesh Cu, Ted Pella). The grids were sealed under vacuum at ~ 40 ℃ in an in-house developed decontamination chamber for > 5 hours before insertion into the TEM to avoid contamination buildup. Annular dark field scanning transmission electron microscopy (ADF-STEM) was performed using Thermo Fisher Scientific Talos F200X G2 S/TEM equipped with a Super-X EDX detector. STEM probe was aligned at 200 keV electron voltage and 10.5 mrad semi-convergence angle at spot size 6 to minimize electron beam damage. Images were acquired with dwell time 2 µs, at a camera length of 98 mm, corresponding to collection angles of bright-field (BF) detector as 8 mrad, dark field (DF2) detector 2 as 11-19 mrad, dark field detector 4 (DF4) as 22-52 mrad and high-angle ADF (HAADF) detector as 56-200 mrad. Pixel size varied between 0.23 Å × 0.23 Å to 0.081 Å × 0.081 Å for acquired atomic resolution images.

TEM imaging for SARS-CoV-2 viral proteins. SARS-CoV-2 viral proteins (20 μL of 0.05 mg/mL) were firstly fixed with a 4% paraformaldehyde solution and adsorbed onto glow discharge grids (300 mesh carbon-coated copper grids) for 5 min and rinsed with three drops of PBS (10 mM, pH 7.4). The grids were then floated onto a phosphotungstic acid solution (10 μL, 10 mM, pH 6.0) for another 5 min, and fixed with glutaraldehyde (0.25%) and blotted dry with filter paper. The images were captured by a TEM (JEOL JEM-2100) operating at an acceleration voltage of 120 kV.

TEM images of chiral NPs bound to SARS-CoV-2 pseudovirus. SARS-CoV-2 pseudovirus (100 μL, 1.0 × 10⁷TU/mL) was first mixed with 4% paraformaldehyde fixation solution for 30 min then the 4% paraformaldehyde was removed by centrifugation (8000 rpm, 20 min, twice) and re-suspended in DPBS. Equal volumes of NPs (1 pM) and pseudovirus solution were mixed at room temperature for 6 h and finally, the chiral NP - pseudovirus complexes was collected by centrifugation (8000 rpm, 10 min). Next, 8 μL of purified sample was dropped onto glow discharge grids (200 mesh carbon-coated copper grids) for 30 min and rinsed with three drops of PBS (10 mM, pH 7.4). Then the rinsed grids were floated with phosphotungstic acid solution (10 μL, 10 mM, pH 6.0) for another 5 min, then blotted dry with filter paper. Finally, the images were captured by TEM (JEOL JEM-2100) operating at an acceleration voltage of 120 kV.

Assembly of Supraparticles (SPs). Supraparticles formed by RBD + chiral NPs were obtained by mixing the RBD (0.3 mg/mL, 50 μL) in PBS (0.01 M, pH 7.4) with chiral NPs (2 nM) for 6 h at 37 ℃. SPs _{(S1 + chiral NPs)} were obtained by mixing the S1 (0.3 mg/mL, 50 μL) in PBS (0.01 M, pH 7.4) with chiral NPs (2 nM) for 6 h at 37 ℃. SPs _{(S + chiral NPs)} were obtained by mixing the S (0.3 mg/mL, 50 μL) in PBS (0.01 M, pH 7.4) with chiral NPs (2 nM) for 6 h at 37 ℃.

Authentic viral inhibition assays. Authentic viral neutralization assays were conducted in BSL3 of Kunming Institute of Zoology. CAS. Detailed protocol followed as: First, Vero E6 cells (2×10⁴ cells/well) were inoculated with to a 96-well plate and cultured overnight at 37°C with 5% CO₂. The different concentrations of L-NPs (100 μL, 24 nM, 12 nM, 6 nM, 3 nM, 1.5 nM, and 0.7 nM, respectively), resuspended in EMEM (0% FBS) with three repeated wells were mixed with SARS-COV-2 (100 μL, resuspended in EMEM with 0% FBS) that multiplicity of infection (MOI) was 0.1, and incubate at 37 °C, 5% CO₂ for 1h. A positive control without L-NPs and a negative control without SARS-COV-2 are set at the same time. The above-mentioned mixture was added into 96-wells plate (200 μL/well) at 37°C, 5% CO₂ and incubate for three days, after the culture medium was removed from cell culture plate. The CCK-8 kit was used to detect the cell viability, and the Bio-Tek microplate detector was used to determine the OD value. The measurement wavelength was 450 nm, and the reference wavelength was 630 nm. Calculate the inhibition rate of the L-NPs on virus replication and determine the antiviral effect of L-NPs.

References

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ACKNOWLEDGMENTS

Chuanlai Xu is grateful to the supporting by the National Natural Science Foundation of China (21977038, 92156003, 51902136). N.A.K is grateful to NSF 1463474 and NSF 1566460 for support. A.F.M. is grateful to MEC/PET for a fellowship and to CNPq for a research fellowship (311353/2019-3). A.F.M. is grateful to the Brazilian funding agencies CAPES, CNPq, and FAPESP (processes 2012/15147-4 and 2013/07296-2) for financial support. We are grateful to the HPC resources provided by the SDumont supercomputer at the National Laboratory for Scientific Computing (LNCC/MCTI, Brazil, http://sdumont.lncc.br) and by the Cloud@UFSCar.

Author Contributions

L.X., H.K., N.A.K. and C.X. conceived the project and designed the experiments. R.G. was responsible for the synthesis, and characterization of the chiral NPs and studied their inhibition effect to virus and viral protein in vitro and in vivo. X.X. was responsible for the expression and purification of viral protein, constructed virus cell model and labeled antibody. P.K. was responsible for the simulation of chiral NPs. Y.L. was responsible for the anti-virus experiments in cells. H.Z. was responsible for the affinity, DLS, Zeta potential experiments. R.G. and X.G, was responsible for the animal experiment. R.G. and X.X. carried out the TEM, TEM tomography, CD and XPS experiments. M.S. carried out the LC-MS, Raman, SAXS and fluorescence experiments. C.L. carried out the SEM imaging. F.M.C. and A.F.M. performed the MD simulations, and analysis the results. M.C., E. S. T. E. and J.M. performed the ML simulations, and analysis the results. L.X., H. K. and N.A.K. conceptualized the work. C.X. supervised the study. L.X., H.K., N.A.K., and C.X. analyzed and discussed the results and wrote the manuscript.

Competing interests

The authors declare no competing interests.

Data availability

The data are available from the corresponding authors upon reasonable request.

There is NO Competing Interest.

VideoFile1TEMReconstructionoftaperedAchiralandChiralNanoparticle.mp4
Video File 1: Three-dimensional reconstruction of achiral and chiral tapered nanoparticles from ADF - STEM images shown in Fig 1 for L-NP and Rac-NP. The solid spheres are locations of atomic columns based on image intensities in ADF-STEM images.
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Supporting Information Targeted Agglutination of Corona Virus by Tapered Chiral Nanoparticles

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Targeted Agglutination of Corona Virus by Tapered Chiral Nanoparticles

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Abstract

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Introduction

Results and Discussion

Tapered CuS Nanoparticles with Multiscale Chirality

Interactions of Chiral NPs and Viral Proteins

Computational Models for NP-Protein Interactions

Inhibition of Binding of Viral Proteins to ACE2 by Chiral NPs in Vitro

Chiral NPs Inhibit SARS-CoV-2 in Living Cells

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References

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