Development of targeted nanoparticles loaded with antiviral drugs for SARS-CoV-2 inhibition

Abstract

Recently, a novel coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has raised global concerns, being the etiological agent of the current pandemic infectious coronavirus disease 2019 (COVID-19). Specific prophylactic treatments like vaccines, have been authorized for use by regulatory bodies in multiple countries, however there is an urgent need to identify new, safe, and targeted therapeutics as post-exposure therapy for COVID-19. Among a plethora of potential pharmacological targets, the angiotensin-converting enzyme 2 (ACE2) membrane receptor, which plays a crucial role in viral entry, is representing an attractive intervention opportunity for SARS-CoV-2 antiviral discovery process. In this scenario, we envisioned that binding to ACE2 by multivalent attachment of ligands to nanocarriers incorporating antiviral therapeutics, it would increase receptor avidity and impart specificity to these nanovectors for host cells, particularly in the pulmonary tract, which is the primary entry route for SARS-CoV-2. Herein, we report the design and development of novel polymeric nanoparticles (NP), densely grafted with various ligands to selectively bind to ACE2, as innovative nanovectors for targeted drug delivery. We first evaluated the impact of these biocompatible targeted NP (TNP) on ligand binding toward ACE2 and measured their competition ability vs a model of spike protein (Lipo-S1). Next, we tested the effectiveness of the most performing nanoprotopype, TNP- 1 , loaded with a model anti -SARS-CoV-2 drug such as remdesivir (RDV), on antiviral activity against SARS-CoV-2 infected Vero E6 cells. The RDV-TNP- 1 exhibited a significantly improved antiviral effect compared to RDV at the same concentration, which resulted in a more potent inhibition of SARS-CoV-2 replication in cell-based assays with respect to unloaded TNP (TNP- 1 E). Interestingly, TNP- 1 E also exhibited a basal antiviral activity, potentially due to a direct competitive mechanism with viral particles for the ACE2 binding site. We also measured the anti-exopeptidase activity of TNP- 1 E against ACE2 protein. Collectively, these insights warrant in-depth preclinical development for our nanoprototypes, for example as potential inhalable drug carriers, with the perspective of a clinical translation.

Identification of a novel immune-inflammatory signature of COVID-19 infections, and evaluation of pharmacokinetics and therapeutic potential of RXn-02, a novel small-molecule derivative of quinolone

“…Several antiviral drugs, including lopinavir, hydroxychloroquine, interferon, molnupiravir, and remdesivir, an RNA-dependent RNA polymerase (RdRp) inhibitor, have been used to treat COVID-19. However, the success of these drugs is limited by poor efficacy, safety concerns, and poor pharmacokinetic (PK) properties [ 27 ]. Molnupiravir, an orally administered anti -SARS-CoV-2 drug, has been reported to be well-tolerated, has oral bioavailability and good safety profile in humans [ 23 , 24 ]; however, its use is associated with risks of tumorigenesis, mutations in sperm precursor cell generation, and to embryo development [ 28 ].…”

A potent virucidal activity of functionalized TiO2 nanoparticles adsorbed with flavonoids against SARS-CoV-2

“…Designer intercepting multiligand interactions during viral entry provides an excellent platform to mitigate the current SARS-CoV-2 pandemic (Sanna et al 2022 ; León-Gutiérrez et al 2021 ). In the current study using molecular docking strategy, we first designed FTNP and further characterized for their antiviral potential against SARS-CoV-2.…”

Engineering viral genomics and nano-liposomes in microfluidic platforms for patient-specific analysis of SARS-CoV-2 variants

“…Drug delivery, efficacy, and toxicity are the three pivotal aspects in the context of immune response in COVID-19 patients. For this reason, drug encapsulation in protein-coated nano-liposomes allows for reduction in drug dosing, toxicity, and high selectivity for specific cellular or viral targets 88 , leading the way to alternative routes of administration, such as inhalation.…”

“…Schematic representation of VoC. Spike proteins derived from the specific VoC can be conjugated with C-Lipo encapsulated with fluorochrome 88 . Abs from the vaccinated or recovered COVID-19 blood can be assessed for their efficiency against the specific VoC.…”