Screening of the NIH Clinical Collection for inhibitors of HIV-1 integrase activity
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 ag...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Academy of Science of South Africa
2018-03-01
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| Series: | South African Journal of Science |
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| Online Access: | https://www.sajs.co.za/article/view/4822 |
| _version_ | 1819261808358195200 |
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| author | Shaakira Abrahams Salerwe Mosebi Muhammed Q. Fish Maria A. Papathanasopoulos Raymond Hewer |
| author_facet | Shaakira Abrahams Salerwe Mosebi Muhammed Q. Fish Maria A. Papathanasopoulos Raymond Hewer |
| author_sort | Shaakira Abrahams |
| collection | DOAJ |
| description | 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 ?M and 9.57±1.62 ?M, 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 (<30% inhibition at 100 ?M) and produced negligible selectivity index values (<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.
Significance:
• This study is the first to screen the US NIH Clinical Collection for potential HIV-1 integrase inhibitors.
• The pervasive nature of promiscuous inhibitors is emphasised. |
| first_indexed | 2024-12-23T19:47:41Z |
| format | Article |
| id | doaj.art-c35c746f12ed405289c9044b1122f6cc |
| institution | Directory Open Access Journal |
| issn | 1996-7489 |
| language | English |
| last_indexed | 2024-12-23T19:47:41Z |
| publishDate | 2018-03-01 |
| publisher | Academy of Science of South Africa |
| record_format | Article |
| series | South African Journal of Science |
| spelling | doaj.art-c35c746f12ed405289c9044b1122f6cc2022-12-21T17:33:30ZengAcademy of Science of South AfricaSouth African Journal of Science1996-74892018-03-011143/45510.17159/sajs.2018/201703244822Screening of the NIH Clinical Collection for inhibitors of HIV-1 integrase activityShaakira Abrahams0Salerwe Mosebi1Muhammed Q. Fish2Maria A. Papathanasopoulos3Raymond Hewer41 Centre for Metal-Based Drug Discovery, Advanced Materials Division, Johannesburg, South Africa 2 Department of Molecular Medicine and Haematology, University of the Witwatersrand Medical School, Johannesburg, South AfricaCentre for Metal-Based Drug Discovery, Advanced Materials Division, Johannesburg, South Africa1 Centre for Metal-Based Drug Discovery, Advanced Materials Division, Johannesburg, South Africa 2 Department of Molecular Medicine and Haematology, University of the Witwatersrand Medical School, Johannesburg, South AfricaDepartment of Molecular Medicine and Haematology, University of the Witwatersrand Medical School, Johannesburg, South AfricaDiscipline of Biochemistry, University of KwaZulu-Natal, Pietermaritzburg, South AfricaDrug 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 ?M and 9.57±1.62 ?M, 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 (<30% inhibition at 100 ?M) and produced negligible selectivity index values (<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. Significance: • This study is the first to screen the US NIH Clinical Collection for potential HIV-1 integrase inhibitors. • The pervasive nature of promiscuous inhibitors is emphasised.https://www.sajs.co.za/article/view/4822drug repurposingstrand transferpan-assay interference compoundsPAINS |
| spellingShingle | Shaakira Abrahams Salerwe Mosebi Muhammed Q. Fish Maria A. Papathanasopoulos Raymond Hewer Screening of the NIH Clinical Collection for inhibitors of HIV-1 integrase activity South African Journal of Science drug repurposing strand transfer pan-assay interference compounds PAINS |
| title | Screening of the NIH Clinical Collection for inhibitors of HIV-1 integrase activity |
| title_full | Screening of the NIH Clinical Collection for inhibitors of HIV-1 integrase activity |
| title_fullStr | Screening of the NIH Clinical Collection for inhibitors of HIV-1 integrase activity |
| title_full_unstemmed | Screening of the NIH Clinical Collection for inhibitors of HIV-1 integrase activity |
| title_short | Screening of the NIH Clinical Collection for inhibitors of HIV-1 integrase activity |
| title_sort | screening of the nih clinical collection for inhibitors of hiv 1 integrase activity |
| topic | drug repurposing strand transfer pan-assay interference compounds PAINS |
| url | https://www.sajs.co.za/article/view/4822 |
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