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Cellular cofactors of lentiviral integrase: from target validation to drug discovery.

Taltynov O, Desimmie BA, Demeulemeester J, Christ F, Debyser Z - Mol Biol Int (2012)

Bottom Line: The nuclear import factor transportin-SR2 (TRN-SR2) has been proposed as another interactor of HIV IN-mediating nuclear import of the virus.Using both proteins as examples, we will describe approaches to be taken to identify and validate novel cofactors as new antiviral targets.Finally, we will highlight recent advances in the design and the development of small-molecule inhibitors binding to the LEDGF/p75-binding pocket in IN (LEDGINs).

View Article: PubMed Central - PubMed

Affiliation: The Laboratory for Molecular Virology and Gene Therapy, KU Leuven, Leuven, Flanders, Belgium.

ABSTRACT
To accomplish their life cycle, lentiviruses make use of host proteins, the so-called cellular cofactors. Interactions between host cell and viral proteins during early stages of lentiviral infection provide attractive new antiviral targets. The insertion of lentiviral cDNA in a host cell chromosome is a step of no return in the replication cycle, after which the host cell becomes a permanent carrier of the viral genome and a producer of lentiviral progeny. Integration is carried out by integrase (IN), an enzyme playing also an important role during nuclear import. Plenty of cellular cofactors of HIV-1 IN have been proposed. To date, the lens epithelium-derived growth factor (LEDGF/p75) is the best studied cofactor of HIV-1 IN. Moreover, small molecules that block the LEDGF/p75-IN interaction have recently been developed for the treatment of HIV infection. The nuclear import factor transportin-SR2 (TRN-SR2) has been proposed as another interactor of HIV IN-mediating nuclear import of the virus. Using both proteins as examples, we will describe approaches to be taken to identify and validate novel cofactors as new antiviral targets. Finally, we will highlight recent advances in the design and the development of small-molecule inhibitors binding to the LEDGF/p75-binding pocket in IN (LEDGINs).

No MeSH data available.


Related in: MedlinePlus

Scheme of nuclear import of the PIC and TRN-SR2 recycling.
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fig5: Scheme of nuclear import of the PIC and TRN-SR2 recycling.

Mentions: TRN-SR2 belongs to the importin-β superfamily of karyopherins [144]. The protein has 975 amino acid residues and is composed of α-helical HEAT repeats. TRN-SR2 is known to import essential splicing factors, the serine/arginine-rich proteins (SR proteins), to the nucleus and is, therefore, involved in the regulation of both constitutive and regulated precursor mRNA splicing. The recognition of the SR-proteins by TRN-SR2 relies on the conserved RS-domain and requires phosphorylation [144–146] although TRN-SR2 is known to import as well proteins not belonging to the SR protein family [147, 148]. The RS domain of SR proteins serves both as an NLS and a subnuclear localization signal [149, 150]. A TRN-SR2 mutant deficient in Ran binding colocalized with SR proteins in nuclear speckles [146]. TRN-SR2 binds its cargo in the cytoplasm and via its interaction with the nuclear pore proteins translocates with cargo to the nucleus (Figure 5). The import is linked to the RanGTP/RanGDP cycle. The small protein Ran GTPase is a member of the Ras protein superfamily and the motor of nuclear protein import. Interaction between Ran and karyopherins is modulated by the state of the bound nucleotide (GTP or GDP). In the nucleus, RanGTP binds to TRN-SR2, displaces the cargo, and then shuttles together with TRN-SR2 to the cytoplasm, where GTP is hydrolyzed to GDP. In the GDP-bound state, Ran dissociates from TRN-SR2 enabling a new round of nuclear import [151]. TRN-SR2 has been shown to interact with Nup62 or its associated complex [146]. Of note, Nup62 is translocated to the cytoplasm and encapsidated into HIV-1 virions during HIV-1 infection [140, 141].


Cellular cofactors of lentiviral integrase: from target validation to drug discovery.

Taltynov O, Desimmie BA, Demeulemeester J, Christ F, Debyser Z - Mol Biol Int (2012)

Scheme of nuclear import of the PIC and TRN-SR2 recycling.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3420096&req=5

fig5: Scheme of nuclear import of the PIC and TRN-SR2 recycling.
Mentions: TRN-SR2 belongs to the importin-β superfamily of karyopherins [144]. The protein has 975 amino acid residues and is composed of α-helical HEAT repeats. TRN-SR2 is known to import essential splicing factors, the serine/arginine-rich proteins (SR proteins), to the nucleus and is, therefore, involved in the regulation of both constitutive and regulated precursor mRNA splicing. The recognition of the SR-proteins by TRN-SR2 relies on the conserved RS-domain and requires phosphorylation [144–146] although TRN-SR2 is known to import as well proteins not belonging to the SR protein family [147, 148]. The RS domain of SR proteins serves both as an NLS and a subnuclear localization signal [149, 150]. A TRN-SR2 mutant deficient in Ran binding colocalized with SR proteins in nuclear speckles [146]. TRN-SR2 binds its cargo in the cytoplasm and via its interaction with the nuclear pore proteins translocates with cargo to the nucleus (Figure 5). The import is linked to the RanGTP/RanGDP cycle. The small protein Ran GTPase is a member of the Ras protein superfamily and the motor of nuclear protein import. Interaction between Ran and karyopherins is modulated by the state of the bound nucleotide (GTP or GDP). In the nucleus, RanGTP binds to TRN-SR2, displaces the cargo, and then shuttles together with TRN-SR2 to the cytoplasm, where GTP is hydrolyzed to GDP. In the GDP-bound state, Ran dissociates from TRN-SR2 enabling a new round of nuclear import [151]. TRN-SR2 has been shown to interact with Nup62 or its associated complex [146]. Of note, Nup62 is translocated to the cytoplasm and encapsidated into HIV-1 virions during HIV-1 infection [140, 141].

Bottom Line: The nuclear import factor transportin-SR2 (TRN-SR2) has been proposed as another interactor of HIV IN-mediating nuclear import of the virus.Using both proteins as examples, we will describe approaches to be taken to identify and validate novel cofactors as new antiviral targets.Finally, we will highlight recent advances in the design and the development of small-molecule inhibitors binding to the LEDGF/p75-binding pocket in IN (LEDGINs).

View Article: PubMed Central - PubMed

Affiliation: The Laboratory for Molecular Virology and Gene Therapy, KU Leuven, Leuven, Flanders, Belgium.

ABSTRACT
To accomplish their life cycle, lentiviruses make use of host proteins, the so-called cellular cofactors. Interactions between host cell and viral proteins during early stages of lentiviral infection provide attractive new antiviral targets. The insertion of lentiviral cDNA in a host cell chromosome is a step of no return in the replication cycle, after which the host cell becomes a permanent carrier of the viral genome and a producer of lentiviral progeny. Integration is carried out by integrase (IN), an enzyme playing also an important role during nuclear import. Plenty of cellular cofactors of HIV-1 IN have been proposed. To date, the lens epithelium-derived growth factor (LEDGF/p75) is the best studied cofactor of HIV-1 IN. Moreover, small molecules that block the LEDGF/p75-IN interaction have recently been developed for the treatment of HIV infection. The nuclear import factor transportin-SR2 (TRN-SR2) has been proposed as another interactor of HIV IN-mediating nuclear import of the virus. Using both proteins as examples, we will describe approaches to be taken to identify and validate novel cofactors as new antiviral targets. Finally, we will highlight recent advances in the design and the development of small-molecule inhibitors binding to the LEDGF/p75-binding pocket in IN (LEDGINs).

No MeSH data available.


Related in: MedlinePlus