HIV1 integrase inhibitors targeting various DDE transposases: Retroviral integration versus RAGmediated recombination (Review).
Mol Med Rep
; 20(6): 4749-4762, 2019 Dec.
Article
em En
| MEDLINE
| ID: mdl-31702817
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. Recombinationactivating 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 Hlike 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 offtarget activity and have been employed to study the interactions between RAG1 recombinase and compounds from three different pharmacologic classes. We demonstrate that strandtransfer 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 HTLV1 integrase opens the way for the development of novel therapies for refractory cancers.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Recombinação Genética
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Proteínas Nucleares
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HIV-1
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Proteínas de Homeodomínio
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Inibidores de Integrase
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Transposases
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Diclorodifenil Dicloroetileno
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Proteínas de Ligação a DNA
Idioma:
En
Revista:
Mol Med Rep
Ano de publicação:
2019
Tipo de documento:
Article