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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

Algorithm to identify and validate novel cofactors as antiviral targets with examples of candidate and validated HIV-1 IN cellular cofactors at particular stages of validation. The algorithm was used in the validation of LEDGF/p75 and TRN-SR2 as cellular cofactors of HIV-1 IN and in validating LEDGF/p75 as an antiviral target. In case of some candidate cofactors, the experimental intervention verifying affect on HIV replication was accompanied by toxicity. These candidates were excluded from follow-up steps of drug target validation.These proteins can still beinvolved in the HIV life cycle but were not considered priority targets.
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Related In: Results  -  Collection


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fig2: Algorithm to identify and validate novel cofactors as antiviral targets with examples of candidate and validated HIV-1 IN cellular cofactors at particular stages of validation. The algorithm was used in the validation of LEDGF/p75 and TRN-SR2 as cellular cofactors of HIV-1 IN and in validating LEDGF/p75 as an antiviral target. In case of some candidate cofactors, the experimental intervention verifying affect on HIV replication was accompanied by toxicity. These candidates were excluded from follow-up steps of drug target validation.These proteins can still beinvolved in the HIV life cycle but were not considered priority targets.

Mentions: The initial discoveries of HMGA1 and BAF were not the result of a systematic search for cellular cofactors of lentiviral integration. The increasing interest in the interactomics of HIV integration and replication has resulted in algorithms for the identification and proper validation of cofactors (Figure 2). Discovery of novel HIV-1 cofactors as potential antiviral targets can be accomplished by different techniques and is often based on the search for specific and direct protein interaction partners by yeast two-hybrid (Y2H) screen or high-throughput coimmunoprecipitation (co-IP) followed by mass spectroscopy. Alternatively, full-genome RNA interference (RNAi) screens can be used to identify genes/proteins involved in HIV integration/replication.


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)

Algorithm to identify and validate novel cofactors as antiviral targets with examples of candidate and validated HIV-1 IN cellular cofactors at particular stages of validation. The algorithm was used in the validation of LEDGF/p75 and TRN-SR2 as cellular cofactors of HIV-1 IN and in validating LEDGF/p75 as an antiviral target. In case of some candidate cofactors, the experimental intervention verifying affect on HIV replication was accompanied by toxicity. These candidates were excluded from follow-up steps of drug target validation.These proteins can still beinvolved in the HIV life cycle but were not considered priority targets.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig2: Algorithm to identify and validate novel cofactors as antiviral targets with examples of candidate and validated HIV-1 IN cellular cofactors at particular stages of validation. The algorithm was used in the validation of LEDGF/p75 and TRN-SR2 as cellular cofactors of HIV-1 IN and in validating LEDGF/p75 as an antiviral target. In case of some candidate cofactors, the experimental intervention verifying affect on HIV replication was accompanied by toxicity. These candidates were excluded from follow-up steps of drug target validation.These proteins can still beinvolved in the HIV life cycle but were not considered priority targets.
Mentions: The initial discoveries of HMGA1 and BAF were not the result of a systematic search for cellular cofactors of lentiviral integration. The increasing interest in the interactomics of HIV integration and replication has resulted in algorithms for the identification and proper validation of cofactors (Figure 2). Discovery of novel HIV-1 cofactors as potential antiviral targets can be accomplished by different techniques and is often based on the search for specific and direct protein interaction partners by yeast two-hybrid (Y2H) screen or high-throughput coimmunoprecipitation (co-IP) followed by mass spectroscopy. Alternatively, full-genome RNA interference (RNAi) screens can be used to identify genes/proteins involved in HIV integration/replication.

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