An Alternative HIV-1 Non-Nucleoside Reverse Transcriptase Inhibition Mechanism: Targeting the p51 Subunit

The ongoing development of drug resistance in HIV continues to push for the need of alternative drug targets in inhibiting HIV. One such target is the Reverse transcriptase (RT) enzyme which is unique and critical in the viral life cycle—a rational target that is likely to have less off-target effec...

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Main Authors:	Kwok-Fong Chan, Chinh Tran-To Su, Alexander Krah, Ser-Xian Phua, Joshua Yi Yeo, Wei-Li Ling, Peter J. Bond, Samuel Ken-En Gan
Format:	Article
Language:	English
Published:	MDPI AG 2020-12-01
Series:	Molecules
Subjects:	HIV novel p51 drug target NNRTIs drug resistance
Online Access:	https://www.mdpi.com/1420-3049/25/24/5902

id	doaj-c29831c314d94287b4bf25a3e2f6ba90
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spelling	doaj-c29831c314d94287b4bf25a3e2f6ba902020-12-14T00:01:07ZengMDPI AGMolecules1420-30492020-12-01255902590210.3390/molecules25245902An Alternative HIV-1 Non-Nucleoside Reverse Transcriptase Inhibition Mechanism: Targeting the p51 SubunitKwok-Fong Chan0Chinh Tran-To Su1Alexander Krah2Ser-Xian Phua3Joshua Yi Yeo4Wei-Li Ling5Peter J. Bond6Samuel Ken-En Gan7Bioinformatics Institute, ASTAR, 30 Biopolis Street, #07-01 Matrix, Singapore 138671, SingaporeBioinformatics Institute, ASTAR, 30 Biopolis Street, #07-01 Matrix, Singapore 138671, SingaporeBioinformatics Institute, ASTAR, 30 Biopolis Street, #07-01 Matrix, Singapore 138671, SingaporeBioinformatics Institute, ASTAR, 30 Biopolis Street, #07-01 Matrix, Singapore 138671, SingaporeBioinformatics Institute, ASTAR, 30 Biopolis Street, #07-01 Matrix, Singapore 138671, SingaporeBioinformatics Institute, ASTAR, 30 Biopolis Street, #07-01 Matrix, Singapore 138671, SingaporeBioinformatics Institute, ASTAR, 30 Biopolis Street, #07-01 Matrix, Singapore 138671, SingaporeBioinformatics Institute, ASTAR, 30 Biopolis Street, #07-01 Matrix, Singapore 138671, SingaporeThe ongoing development of drug resistance in HIV continues to push for the need of alternative drug targets in inhibiting HIV. One such target is the Reverse transcriptase (RT) enzyme which is unique and critical in the viral life cycle—a rational target that is likely to have less off-target effects in humans. Serendipitously, we found two chemical scaffolds from the National Cancer Institute (NCI) Diversity Set V that inhibited HIV-1 RT catalytic activity. Computational structural analyses and subsequent experimental testing demonstrated that one of the two chemical scaffolds binds to a novel location in the HIV-1 RT p51 subunit, interacting with residue Y183, which has no known association with previously reported drug resistance. This finding supports the possibility of a novel druggable site on p51 for a new class of non-nucleoside RT inhibitors that may inhibit HIV-1 RT allosterically. Although inhibitory activity was shown experimentally to only be in the micromolar range, the scaffolds serve as a proof-of-concept of targeting the HIV RT p51 subunit, with the possibility of medical chemistry methods being applied to improve inhibitory activity towards more effective drugs.https://www.mdpi.com/1420-3049/25/24/5902HIVnovel p51 drug targetNNRTIsdrug resistance
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Kwok-Fong Chan Chinh Tran-To Su Alexander Krah Ser-Xian Phua Joshua Yi Yeo Wei-Li Ling Peter J. Bond Samuel Ken-En Gan
spellingShingle	Kwok-Fong Chan Chinh Tran-To Su Alexander Krah Ser-Xian Phua Joshua Yi Yeo Wei-Li Ling Peter J. Bond Samuel Ken-En Gan An Alternative HIV-1 Non-Nucleoside Reverse Transcriptase Inhibition Mechanism: Targeting the p51 Subunit Molecules HIV novel p51 drug target NNRTIs drug resistance
author_facet	Kwok-Fong Chan Chinh Tran-To Su Alexander Krah Ser-Xian Phua Joshua Yi Yeo Wei-Li Ling Peter J. Bond Samuel Ken-En Gan
author_sort	Kwok-Fong Chan
title	An Alternative HIV-1 Non-Nucleoside Reverse Transcriptase Inhibition Mechanism: Targeting the p51 Subunit
title_short	An Alternative HIV-1 Non-Nucleoside Reverse Transcriptase Inhibition Mechanism: Targeting the p51 Subunit
title_full	An Alternative HIV-1 Non-Nucleoside Reverse Transcriptase Inhibition Mechanism: Targeting the p51 Subunit
title_fullStr	An Alternative HIV-1 Non-Nucleoside Reverse Transcriptase Inhibition Mechanism: Targeting the p51 Subunit
title_full_unstemmed	An Alternative HIV-1 Non-Nucleoside Reverse Transcriptase Inhibition Mechanism: Targeting the p51 Subunit
title_sort	alternative hiv-1 non-nucleoside reverse transcriptase inhibition mechanism: targeting the p51 subunit
publisher	MDPI AG
series	Molecules
issn	1420-3049
publishDate	2020-12-01
description	The ongoing development of drug resistance in HIV continues to push for the need of alternative drug targets in inhibiting HIV. One such target is the Reverse transcriptase (RT) enzyme which is unique and critical in the viral life cycle—a rational target that is likely to have less off-target effects in humans. Serendipitously, we found two chemical scaffolds from the National Cancer Institute (NCI) Diversity Set V that inhibited HIV-1 RT catalytic activity. Computational structural analyses and subsequent experimental testing demonstrated that one of the two chemical scaffolds binds to a novel location in the HIV-1 RT p51 subunit, interacting with residue Y183, which has no known association with previously reported drug resistance. This finding supports the possibility of a novel druggable site on p51 for a new class of non-nucleoside RT inhibitors that may inhibit HIV-1 RT allosterically. Although inhibitory activity was shown experimentally to only be in the micromolar range, the scaffolds serve as a proof-of-concept of targeting the HIV RT p51 subunit, with the possibility of medical chemistry methods being applied to improve inhibitory activity towards more effective drugs.
topic	HIV novel p51 drug target NNRTIs drug resistance
url	https://www.mdpi.com/1420-3049/25/24/5902
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An Alternative HIV-1 Non-Nucleoside Reverse Transcriptase Inhibition Mechanism: Targeting the p51 Subunit

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