HIV‑1 integrase inhibitors targeting various DDE transposases: Retroviral integration versus RAG‑mediated recombination (Review)

Abstract

Transposases are ubiquitous mobile genetic elements responsible for genome development, driving rearrangements, such as insertions, deletions and translocations. across species evolution, some transposases are tamed by their host and are made part of complex cellular systems. The proliferation of retroviruses is also dependent on transposase related enzymes termed integrases. recombination-activating gene protein (raG)1 and metnase are just two examples of transposase domestication and together with retroviral integrases (ins), they belong to the dde polynucleotidyl transferases superfamily. They share mechanistic and structural features linked to the rnase H-like fold, harboring a dde(d) metal dependent catalytic motif. recent antiretroviral compounds target the catalytic domain of integrase, but they also have the potential of inhibiting other related enzymes. in this review, we report the activity of different classes of integrase inhibitors on various dde transposases. computational simulations are useful to predict the extent of off-target activity and have been employed to study the interactions between raG1 recombinase and compounds from three different pharmacologic classes. We demonstrate that strand-transfer inhibitors display a higher affinity towards the raG1 rnase H domain, as suggested by experimental data compared to allosteric inhibitors. While interference with raG1 and 2 recombination is associated with a negative impact on immune function, the inhibition of metnase or HTlV-1 integrase opens the way for the development of novel therapies for refractory cancers. Contents 1. introduction 2. docking simulations and conformations 3. recombination protein raG: a domesticated transposase 4. raG recombination versus retroviral integration 5. in inhibitors 6. HiV-1 in inhibitors potentially interfere with raGmediated recombination 7. docking simulations of in inhibitors on raG1 dimer 8. HiV-1 in inhibitors interfere with various polynucleotidyl transferases 9. conclusions

Retrotransposons facilitates tissue specific horizontal transfer of circulating tumor DNA between human cells

“…To evaluate the role of retrotransposons in horizontal gene transfer of ctDNA, we analyzed the impact of inhibiting reverse transcription or integrases on ctDNA integration. Therefore, before adding the ctDNA to the culture media, we treated the multiple myeloma (MM1s), pancreatic cancer (MIA), and colon cancer (HCT116) cell lines with the reverse-transcriptase inhibitors zidovudine (AZT) or didanosine (DDI), as well as with the integrase inhibitor raltegravir 23 . When compared to the no-treatment control, the use of the reverse transcriptase and integrase inhibitors significantly decreased ctDNA chromatid integration (Figure 4D and Supplemental Figure 2A), giving proof that retrotransposons are crucial for ctDNA integration into the host cell's genome.…”

HIV‐1 integrase inhibitor raltegravir promotes DNA damage‐induced apoptosis in multiple myeloma

“…However, elvitegravir and dolutegravir, two other FDA‐approved retroviral integrases, have recently been demonstrated to inhibit V(D)J recombination and significantly reduce mature B lymphocytes in vivo, unlike raltegravir (Nilavar et al, 2020). Computational docking simulations predicted the highest frequency of interaction between RAG1 recombinase and raltegravir among the other integrase inhibitors (Musat et al, 2019). As RAG1 and RAG2 might be the possible targets of raltegravir, the mRNA expression of RAG1 but not RAG2 was upregulated in the CD138+ myeloma cells compared with CD138‐ non‐myeloma cells derived from NDMM patients.…”

Prolonged neutropenia in patients with lymphoma treated with antiretroviral therapy: Raltegravir too? A single‐case report

“…Notably, integrase inhibitors could potentially interact with recombination activating gene 1 (RAG1), given similar mechanistic and structural characteristics shared with viral integrase. 8 Furthermore, neutrophils express RAG1, and Tlymphocytes may inhibit apoptosis via activation of this receptor. 9 Thus, it could be speculated that integrase inhibitors may cause neutropenia through disruption of this pathway.…”

“…According to these data, raltegravir is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes and seems unlikely to cause neutropenia by DDIs. Notably, integrase inhibitors could potentially interact with recombination activating gene 1 (RAG1), given similar mechanistic and structural characteristics shared with viral integrase 8 . Furthermore, neutrophils express RAG1, and T‐lymphocytes may inhibit apoptosis via activation of this receptor 9 .…”