Cabotegravir is an Orally Active HIV Integrase Inhibitor for AIDS Research

By Edward Jenner 2023-09-04 #AIDS, #Cabotegravir, #GSK-1265744, #HIV, #Retroviral integrase

Retroviral integrase (IN) is an enzyme produced by a retrovirus (such as HIV) that integrates (forms covalent links between) its genetic information into that of the host cell it infects.

HIV integrase is a 32kDa viral protein. And it consists of three domains- N-terminus, catalytic core domain and C-terminus, which each have distinct properties and functions contributing to the efficacy of HIV integrase. The N-terminal consists of 50 amino acid residues. In addition, it contains conserved histidine, histidine, cytosine, and cytosine sequences, which can chelate zinc ions and further enhance the enzymatic activity of the catalytic core domain. As metal chelation is vital in integrase efficacy, it is a target for the development of retroviral therapies. The catalytic core domain, like the N-terminus, contains highly conserved amino acid residues -Asp64, Asp116, Glu152- as the conserved DDE (Asp-Asp-Glu) motif contributes to the endonuclease and polynucleotide transferase functions of integrase. Mutations in these regions inactivates integrase and prevents genome integration. The C-terminus domain binds to host DNA non-specifically and stabilizes the integration complex.

Cabotegravir is a HIV Integrase Inhibitor for AIDS Research

Cabotegravir (GSK-1265744) is a orally active and long-acting HIV integrase strand transfer inhibitor for AIDS Research. And it’s also an organic anion transporter 1/3 (OAT1/OAT3) inhibitor. In addition, it has IC₅₀ values of 2.5 nM, 0.41 μM and 0.81 μM for HIV_ADA, OAT3 and OAT1, respectively. And it is primarily metabolized by uridine diphosphate glucuronosyltransferase (UGT) 1A1. Therefore, the potential for interactions with other antiretroviral drugs (ARVs) is low.

In vitro, Cabotegravir (GSK-1265744) inhibits the HIV-1 integrase catalyzed strand transfer reaction with an IC₅₀ of 3.0 nM. What’s more, the antiviral EC₅₀ against HIV-1 Ba-L is 0.22 nM and that against NL432 is 0.34 nM in PBMCs, 0.57 nM using CellTiter-Glo and 1.3 nM using MTT in MT-4, and 0.5 nM in the PHIV assay, which uses a pseudotyped self-inactivating virus. In vivo, the half-life of Cabotegravir is up to 54 days in mice. Cabotegravir (25 or 50 mg/kg; i.v.; single dose or twice) protects Macaques against intravenous challenge with SIVmac251.

In conclusion, Cabotegravir is a HIV integrase inhibitor for AIDS research.

Reference:

[1] Biomaterials. 2018 Jan;151:53-65.

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[3] Antimicrob Agents Chemother. 2015 Jan;59(1):397-406.