Abstract
Integrase inhibitors are a class of antiretroviral drugs used for the treatment of AIDS that target HIV integrase, an enzyme responsible for integration of viral cDNA into host genome. RAG1, a critical enzyme involved in V(D)J recombination exhibits structural similarity to HIV integrase. We find that two integrase inhibitors, Raltegravir and Elvitegravir, interfered with the physiological functions of RAGs such as binding, cleavage and hairpin formation at the recombination signal sequence (RSS), though the effect of Raltegravir was limited. Circular dichroism studies demonstrated a distinct change in the secondary structure of RAG1 central domain (RAG1 shares DDE motif amino acids with integrases), and when incubated with Elvitegravir, an equilibrium dissociation constant (Kd) of 32.53±2.9 μM was determined by Biolayer interferometry, leading to inhibition of its binding to DNA. Besides, using extrachromosomal assays, we show that Elvitegravir inhibited both coding and signal joint formation in pre-B cells. Importantly, treatment with Elvitegravir resulted in significant reduction of mature B lymphocytes in 70% of mice studied. Thus, our study suggests a potential risk associated with the use of Elvitegravir as an antiretroviral drug, considering the evolutionary and structural similarities between HIV integrase and RAGs.
Highlights
Human immunodeficiency virus (HIV) infection leads to acquired immunodeficiency syndrome (AIDS)
Since recombination activating gene 1 (RAG1) shares structural and functional similarity with HIV integrase (Figure 1), we tested whether Raltegravir and Elvitegravir, affect the sequencespecific action of RAGs (Figure 2a and b)
A distinct inhibition in RAG binding to recombination signal sequence (RSS) by Elvitegravir was seen from a concentration of 200 μM onwards, inhibition of cleavage was observed at concentrations as low as 50 μM (Figure 2g and h)
Summary
Human immunodeficiency virus (HIV) infection leads to acquired immunodeficiency syndrome (AIDS). In the presence of Ca2+, integrase binds to DNA and forms protein–DNA complexes, which cannot catalyse cleavage reactions, a mechanism analogous to that of RAGs.[12] RAG1 and integrase harbour a conserved catalytic DDE motif and the carboxyl groups of the amino acids harbouring this motif bind one or more divalent ions like Mg2+, which are essential for the activity of both the proteins.[10,13]. Elvitegravir (GS-9137), a quinolone carboxylic acid strand-transferspecific inhibitor by Gilead Sciences is approved by FDA for therapeutic use (Figure 2b). Both these compounds share a β-hydroxy-ketone structural motif that possesses. The study was prematurely terminated because of difficulty in recruitment of volunteers (ClinicalTrials.gov Identifier: NCT00785967)
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