Pharmacophore and structure-activity relationships of integrase inhibition within a dual inhibitor scaffold of HIV reverse transcriptase and integrase

Zhengqiang Wang; Jing Tang; Christine E. Salomon; Christine D. Dreis; Robert Vince

doi:10.1016/j.bmc.2010.05.004

Pharmacophore and structure-activity relationships of integrase inhibition within a dual inhibitor scaffold of HIV reverse transcriptase and integrase

Zhengqiang Wang, Jing Tang, Christine E. Salomon, Christine D. Dreis, Robert Vince

Center for Drug Design

Research output: Contribution to journal › Article › peer-review

46 Scopus citations

Abstract

Rational design of dually active inhibitors against human immunodeficiency virus (HIV) reverse transcriptase (RT) and integrase (IN) has proved viable with 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) type of non-nucleoside RT inhibitors (NNRTIs). To establish the pharmacophore and study the structure-activity relationships (SAR) of integrase inhibition within a previously disclosed RT/IN dual inhibitor scaffold, new analogues featuring substitution at different sites of the HEPT ring were designed and synthesized. These studies have revealed an IN inhibition pharmacophore that is merged with the known RT pharmacophore through a shared C-6 benzyl group. Further SAR also demonstrated that optimal IN inhibition within our dual inhibitor scaffold requires a regiospecific (N-1) diketoacid (DKA)-carrying pendant with a certain length.

Original language	English (US)
Pages (from-to)	4202-4211
Number of pages	10
Journal	Bioorganic and Medicinal Chemistry
Volume	18
Issue number	12
DOIs	https://doi.org/10.1016/j.bmc.2010.05.004
State	Published - Jun 15 2010

Bibliographical note

Funding Information:
This research was supported by the Center for Drug Design at the University of Minnesota . We thank Dr. Yuk Sham for helpful discussion, Daniel Wilson for assistance in IN assay, Roger Ptak at Southern Research Institute for cell-based HIV assay, Dr. Robert Craigie of NIH for the integrase plasmid and Dr. William Shannon for consultation.

Keywords

Diketoacid
HIV
Integrase
Pharmacophore
SAR

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmc.2010.05.004

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abstract = "Rational design of dually active inhibitors against human immunodeficiency virus (HIV) reverse transcriptase (RT) and integrase (IN) has proved viable with 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) type of non-nucleoside RT inhibitors (NNRTIs). To establish the pharmacophore and study the structure-activity relationships (SAR) of integrase inhibition within a previously disclosed RT/IN dual inhibitor scaffold, new analogues featuring substitution at different sites of the HEPT ring were designed and synthesized. These studies have revealed an IN inhibition pharmacophore that is merged with the known RT pharmacophore through a shared C-6 benzyl group. Further SAR also demonstrated that optimal IN inhibition within our dual inhibitor scaffold requires a regiospecific (N-1) diketoacid (DKA)-carrying pendant with a certain length.",

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author = "Zhengqiang Wang and Jing Tang and Salomon, {Christine E.} and Dreis, {Christine D.} and Robert Vince",

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AU - Salomon, Christine E.

AU - Dreis, Christine D.

AU - Vince, Robert

N1 - Funding Information: This research was supported by the Center for Drug Design at the University of Minnesota . We thank Dr. Yuk Sham for helpful discussion, Daniel Wilson for assistance in IN assay, Roger Ptak at Southern Research Institute for cell-based HIV assay, Dr. Robert Craigie of NIH for the integrase plasmid and Dr. William Shannon for consultation.

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N2 - Rational design of dually active inhibitors against human immunodeficiency virus (HIV) reverse transcriptase (RT) and integrase (IN) has proved viable with 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) type of non-nucleoside RT inhibitors (NNRTIs). To establish the pharmacophore and study the structure-activity relationships (SAR) of integrase inhibition within a previously disclosed RT/IN dual inhibitor scaffold, new analogues featuring substitution at different sites of the HEPT ring were designed and synthesized. These studies have revealed an IN inhibition pharmacophore that is merged with the known RT pharmacophore through a shared C-6 benzyl group. Further SAR also demonstrated that optimal IN inhibition within our dual inhibitor scaffold requires a regiospecific (N-1) diketoacid (DKA)-carrying pendant with a certain length.

AB - Rational design of dually active inhibitors against human immunodeficiency virus (HIV) reverse transcriptase (RT) and integrase (IN) has proved viable with 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) type of non-nucleoside RT inhibitors (NNRTIs). To establish the pharmacophore and study the structure-activity relationships (SAR) of integrase inhibition within a previously disclosed RT/IN dual inhibitor scaffold, new analogues featuring substitution at different sites of the HEPT ring were designed and synthesized. These studies have revealed an IN inhibition pharmacophore that is merged with the known RT pharmacophore through a shared C-6 benzyl group. Further SAR also demonstrated that optimal IN inhibition within our dual inhibitor scaffold requires a regiospecific (N-1) diketoacid (DKA)-carrying pendant with a certain length.

KW - Diketoacid

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KW - Integrase

KW - Pharmacophore

KW - SAR

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Pharmacophore and structure-activity relationships of integrase inhibition within a dual inhibitor scaffold of HIV reverse transcriptase and integrase

Abstract

Bibliographical note

Keywords

UN SDGs

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