The Evaluation of Statins as Potential Inhibitors of the LEDGF/p75–HIV‐1 Integrase interaction

Harrison, Angela T.; Kriel, Frederik H.; Papathanasopoulos, Maria A.; Mosebi, Salerwe; Abrahams, Shaakira; Hewer, Raymond

doi:10.1111/cbdd.12384

Cited by 12 publications

(8 citation statements)

References 21 publications

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“…The cellular protein lens epithelium derived growth factor (LEDGF/p75) is essential for integration by binding IN and tethering it to the chromosomes . Several highly potent small molecule inhibitors of the IN‐LEDGF/p75 interactions were already reported . We have previously developed several linear and cyclic peptidic IN inhibitors based on the IN‐binding loops of LEDGF/p75 .…”

Section: Introductionmentioning

confidence: 99%

“…[35][36][37] Several highly potent small molecule inhibitors of the IN-LEDGF/p75 interactions were already reported. [38][39][40][41][42][43][44][45] We have previously developed several linear and cyclic peptidicI Ni nhibitors based on the IN-binding loopso fL EDGF/ p75. [46] The most potent inhibitors were the LEDGF 361-370 peptide [38][39][40][41][42][43][44][45] and its cyclic derivatives.…”

Section: Introductionmentioning

confidence: 99%

“…[38][39][40][41][42][43][44][45] We have previously developed several linear and cyclic peptidicI Ni nhibitors based on the IN-binding loopso fL EDGF/ p75. [46] The most potent inhibitors were the LEDGF 361-370 peptide [38][39][40][41][42][43][44][45] and its cyclic derivatives. [47][48][49][50][51][52][53] Recently we have developed an ew peptide cyclization method, in which cyclization between al ysine residue and an N-terminals uccinimide moiety occurs in situ duringt he TFA-mediated peptided eprotection/cleavage step.…”

Section: Introductionmentioning

confidence: 99%

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Covalent Inhibition of HIV‐1 Integrase by N‐Succinimidyl Peptides

et al. 2016

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We present a new approach for the covalent inhibition of HIV-1 integrase (IN) by an LEDGF/p75-derived peptide modified with an N-terminal succinimide group. The covalent inhibition is mediated by direct binding of the succinimide to the amine group of a lysine residue in IN. The peptide serves as a specific recognition sequence for the target protein, while the succinimide serves as the binding moiety. The combination of a readily synthesizable peptide precursor with easy and efficient binding to the target protein makes this approach a promising new strategy for designing lead compounds.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Covalent Inhibition of HIV‐1 Integrase by N‐Succinimidyl Peptides

et al. 2016

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“…7,8 Recombinant His-tagged HIV-1 IN was expressed and purified as previously described. 9 Briefly, wild-type HIV-1 IN was overexpressed in E. coli BL21 (DE3) bacterial cells using the NL4-3 histidine (HIS)-tagged HIV-1 IN coding sequence, pINSD, cloned into pET15B (Merck Millipore, Darmstadt, Germany). Cells were grown to logarithmic phase in Luria-Bertani medium and induced with 1 mM isopropyl-thiogalactoside.…”

Section: Expression and Purification Of Recombinant Hiv-1 Integrasementioning

confidence: 99%

Screening of the NIH Clinical Collection for inhibitors of HIV-1 integrase activity

Abrahams¹,

Mosebi²,

Fish³

et al. 2018

S. Afr. J. Sci.

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Drug repurposing offers a validated approach to reduce drug attrition within the drug discovery and development pipeline through the application of known drugs and drug candidates to treat new indications. Full exploitation of this strategy necessitates the screening of a vast number of molecules against an extensive number of diseases of high burden or unmet need and the subsequent dissemination of the findings. In order to contribute to endeavours within this field, we screened the 727 compounds comprising the US National Institutes of Health (NIH) Clinical Collection through an HIV-1 (human immunodeficiency virus type 1) integrase stand transfer inhibition assay on an automated scintillation proximity assay platform. Only two compounds were identified within the initial screen, with cefixime trihydrate and epigallocatechin gallate found to reduce integrase strand transfer activity at IC50 values of 6.03±1.29 μM and 9.57±1.62 μM, respectively. However, both cefixime trihydrate and epigallocatechin gallate retained their low micromolar inhibitory activity when tested against a raltegravir-resistant integrase double mutant (FCIC50 values of 0.83 and 0.06, respectively), were ineffective in an orthogonal strand transfer ELISA (less than 30% inhibition at 100 μM) and produced negligible selectivity index values (less than 1) in vitro. While no useful inhibitors of HIV-1 integrase strand transfer activity were found within the NIH Clinical Collection, the identification of two assay-disrupting molecules demonstrates the importance of consideration of non-specific inhibitors in drug repurposing screens.

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“…We collected 274 HIV-1 integrase LEDGF/p75 inhibitors from the literature. [2,3,[12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] The activities, from 0.019 mM to 170.7 mM, spanned 4 orders of magnitude. Taking 20 mM as the threshold, the dataset was divided into two subdatasets.…”

Section: Datasetmentioning

confidence: 99%

Study of Structure-active Relationship for Inhibitors of HIV-1 Integrase LEDGF/p75 Interaction by Machine Learning Methods

Yan

2017

Mol. Inf.

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HIV-1 integrase (IN) is a promising target for anti-AIDS therapy, and LEDGF/p75 is proved to enhance the HIV-1 integrase strand transfer activity in vitro. Blocking the interaction between IN and LEDGF/p75 is an effective way to inhibit HIV replication infection. In this work, 274 LEDGF/p75-IN inhibitors were collected as the dataset. Support Vector Machine (SVM), Decision Tree (DT), Function Tree (FT) and Random Forest (RF) were applied to build several computational models for predicting whether a compound is an active or weakly active LEDGF/p75-IN inhibitor. Each compound is represented by MACCS fingerprints and CORINA Symphony descriptors. The prediction accuracies for the test sets of all the models are over 70 %. The best model Model 3B built by FT obtained a prediction accuracy and a Matthews Correlation Coefficient (MCC) of 81.08 % and 0.62 on test set, respectively. We found that the hydrogen bond and hydrophobic interactions are important for the bioactivity of an inhibitor.

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The Evaluation of Statins as Potential Inhibitors of the LEDGF/p75–HIV‐1 Integrase interaction

Cited by 12 publications

References 21 publications

Covalent Inhibition of HIV‐1 Integrase by N‐Succinimidyl Peptides

Covalent Inhibition of HIV‐1 Integrase by N‐Succinimidyl Peptides

Screening of the NIH Clinical Collection for inhibitors of HIV-1 integrase activity

Study of Structure-active Relationship for Inhibitors of HIV-1 Integrase LEDGF/p75 Interaction by Machine Learning Methods

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