Bismuth-based drugs and agents as SARS-CoV-2 agents and nephrotoxicity scavengers

Abstract

Metal compounds have long been used in clinic for the treatment and diagnosis of various diseases (e.g., platinum-based anti-cancer drugs, bismuth-based anti-ulcer drugs and gadolinium-based MRI contrast agent) and have enormous potential for emerging infectious diseases. For example, COVID-19 pandemic unprecedently triggers global public health issue while effective treatment options remain limited. In Chapter 2, a primary screening has been performed over a series of metallodrugs against SARS-CoV-2 infection, and bismuth-containing drug ranitidine bismuth citrate (RBC) has been demonstrated to be a potent inhibitor against helicase of SARS-CoV-2 with the ATPase activity (IC50 = 0.69 µM) and DNA-unwinding activity (IC50 = 1.2 µM) being remarkably inhibited via structural zinc(II) displacement route. Meanwhile, RBC could disarm SARS-CoV-2 effectively with ~10,000-fold reduction of viral gene copies in the cell culture and supernatant. In animal infection model, intraperitoneal treatment of RBC potently suppresses SARS-CoV-2 replication and relieves virus-associated pneumonia which sheds light on a novel application of bismuth(III) drugs or other related compounds for the treatment of SARS-CoV-2 infection. In Chapter 3, a cocktail therapy consisting of clinically used drugs, e.g., colloidal bismuth subcitrate (CBS) and N-acetyl-L-cysteine (NAC) has been developed as effective oral remedy which could be rapidly deployed to outpatients. NAC prevents the hydrolysis of bismuth drugs at gastric pH with approximately 100% bismuth(III) remained in the supernatant and improves the systemic uptake of bismuth compounds in vivo. Importantly, oral administration of CBS and NAC combination significantly reduced pulmonary viral loads with~15-fold reduction in pulmonary SARS-CoV-2 RNA copies and mitigated virus-associated pneumonia in a hamster model of SARS-CoV-2 pathogenesis. The mechanistic studies show that Bi(NAC)3, the active component of CBS-NAC combination, broadly targets key conserved cysteine proteases including papain-like protease (IC50= 1.00 μM), main protease(IC50=21.10 μM), helicase and angiotensin-converting enzyme 2, offering a general strategy for combatting future coronavirus diseases. In Chapter 4, a powder formulation of RBC produced by spray freeze drying technique was developed as the third generation of antivirals. The formulation containing 20% (w/w) RBC with the presence of 10% (w/w) leucine as hydrophobic surfactant and 70% (w/w) mannitol as main excipient prepared with a two-fluid nozzle exhibits optimal aerosol performance with fine particle fraction over 40%. Pharmacokinetic study shows prolonged stay of bismuth(III) content in the lungs and bronchoalveolar lavage fluid following intratracheal administration. More importantly, intratracheal administration of 5 mg kg-1 formulated RBC led to 9.11-fold reduction in viral load in Delta-infected hamsters. In Chapter 5, a novel nephroprotectant, Bi(III) porphyrin (Bi(TPP)), has been studied since it could alleviate the cisplatin-induced (CDDP) nephrotoxicity in acute kidney model with a survival rate of 66.7% while do not compromise the anti-neoplastic effects of CDDP. The underlying mechanism of this hit is mediated not primarily owing to the induction of metallothionein but rather to other multiple protective mechanisms including maintaining cellular redox and mitochondrial function, facilitating renal platinum excretion and attenuating caspase-dependent apoptosis caspases. Collectively, these findings validate the potential to expedite the development of bismuth(III) based agents and provide novel insights into the molecular basis of metallodrugs and stimulate translational research to flourish.