Triazolyl Ru(II), Os(II), and Ir(III) complexes as potential HIV-1 inhibitors

Area of Science:

• Medicinal Chemistry
• Virology
• Nanotechnology

Background:

• Human immunodeficiency virus (HIV) infection remains a significant global health concern.
• Combination antiretroviral therapy has improved outcomes but is associated with side effects, driving the need for new treatments.
• Metal-based complexes with anticancer properties are being explored for other therapeutic applications.

Purpose of the Study:

• To investigate the anti-HIV activity of three N-aryl-1H-1,2,3-triazole-based cyclometalated metal complexes (Ruthenium-(II), Iridium-(III), and Osmium-(II)).
• To evaluate the efficacy of these complexes against HIV-1 subtypes C and A pseudoviruses.
• To determine the mechanism of action and cellular toxicity of the investigated complexes.

Main Methods:

• In vitro testing of three metal complexes (Ru(II), Ir(III), Os(II)) against HIV-1 subtype C (CAP 210, Du 156) and subtype A (Q 23) pseudoviruses.
• Determination of half-maximal inhibitory concentration (IC50) values for viral entry inhibition.
• Cytotoxicity assays on mammalian cells.
• In silico molecular docking studies using Maestro 12.2 to predict the mechanism of action.

Main Results:

• All three metal complexes demonstrated significant inhibition of viral entry at low micromolar concentrations (IC50 values ranging from 2.35 to 8.09 µM).
• The N-aryl-1H-1,2,3-triazole-based cyclometalated complexes showed potent activity, with no significant inhibition observed from the ligand alone.
• The tested concentrations of the complexes were non-toxic to mammalian cells.
• In silico docking suggested that the antiviral activity may stem from interactions with the CCR5 co-receptor, specifically involving key amino acids (Glu 283, Tyr 251, Tyr 108) crucial for gp120 binding.

Conclusions:

• N-aryl-1H-1,2,3-triazole-based cyclometalated Ruthenium-(II), Iridium-(III), and Osmium-(II) complexes are effective inhibitors of HIV-1 entry.
• These metal complexes exhibit a promising safety profile, being non-toxic to mammalian cells at effective concentrations.
• The findings suggest a potential therapeutic strategy targeting the CCR5 co-receptor for HIV treatment.