Title:The Development of HEPT-Type HIV Non-Nucleoside Reverse Transcriptase Inhibitors and Its Implications for DABO Family
Volume: 18
Issue: 27
Author(s): Wenmin Chen, Peng Zhan, Jingde Wu, Zhenyu Li and Xinyong Liu
Affiliation:
Keywords:
HIV-1, HEPT, NNRTI, DABO, structure-activity relationship, drug design, dual inhibitor, pyrimidinedione, X-crystallographic studies, designed multiple ligands (DMLs).
Abstract: 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) was discovered as the first HIV-1 non-nucleoside reverse transcriptase
inhibitors (NNRTIs) in 1989. The research on HEPT derivatives (HEPTs) has been lasted for more than 20 years and HEPT
family is probably the most investigated NNRTI. Extensive molecular modifications on HEPT have led to many highly potent compounds
with broad-resistance spectrum and optimal pharmacokinetic profiles. Moreover, X-crystallographic studies of HEPTs/RT complexes
revealed the binding mode of HEPTs and the action mechanism of NNRTI, which has greatly facilitated the design of novel
NNRTIs. Recently, the development of HEPTs was accelerated by the application of the “follow-on”-based chemical evolution strategies,
such as designed multiple ligands (DMLs) and molecular hybridization (MH). Herein, this article will provide an insight into the
development of HEPTs, including structural modifications, crystal structure of RT complexed with HEPTs and its structure-activity relationship
(SAR). Additionally, this review also covers the emerging HEPT related dual inhibitors and HEPT-pyridinone hybrids, as well
as the contributions of HEPTs to the development of dihydro-alkoxy-benzyl-oxopyrimidine (DABO) family, thus highlighting the importance
of HEPTs on the development of NNRTIs.
