Open Access

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

  • Authors:
    • Mihaela Georgiana Mușat
    • George Mihai Nițulescu
    • Marius Surleac
    • Aristidis Tsatsakis
    • Demetrios A. Spandidos
    • Denisa Margină
  • View Affiliations

  • Published online on: October 30, 2019     https://doi.org/10.3892/mmr.2019.10777
  • Pages: 4749-4762
  • Copyright: © Mușat et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.
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December-2019
Volume 20 Issue 6

Print ISSN: 1791-2997
Online ISSN:1791-3004

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Spandidos Publications style
Mușat MG, Nițulescu GM, Surleac M, Tsatsakis A, Spandidos DA and Margină D: HIV‑1 integrase inhibitors targeting various DDE transposases: Retroviral integration versus RAG‑mediated recombination (Review). Mol Med Rep 20: 4749-4762, 2019
APA
Mușat, M.G., Nițulescu, G.M., Surleac, M., Tsatsakis, A., Spandidos, D.A., & Margină, D. (2019). HIV‑1 integrase inhibitors targeting various DDE transposases: Retroviral integration versus RAG‑mediated recombination (Review). Molecular Medicine Reports, 20, 4749-4762. https://doi.org/10.3892/mmr.2019.10777
MLA
Mușat, M. G., Nițulescu, G. M., Surleac, M., Tsatsakis, A., Spandidos, D. A., Margină, D."HIV‑1 integrase inhibitors targeting various DDE transposases: Retroviral integration versus RAG‑mediated recombination (Review)". Molecular Medicine Reports 20.6 (2019): 4749-4762.
Chicago
Mușat, M. G., Nițulescu, G. M., Surleac, M., Tsatsakis, A., Spandidos, D. A., Margină, D."HIV‑1 integrase inhibitors targeting various DDE transposases: Retroviral integration versus RAG‑mediated recombination (Review)". Molecular Medicine Reports 20, no. 6 (2019): 4749-4762. https://doi.org/10.3892/mmr.2019.10777