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Kundarapu M.,Rega Institute for Medical Research | Marchand D.,Center for Innovation and Stimulation of Medicines Development | Dumbre S.G.,Rega Institute for Medical Research | Herdewijn P.,Rega Institute for Medical Research
Tetrahedron Letters | Year: 2011

A series of 2′ functionalized acyclic nucleoside phosphonate derivatives of 1-[3′-(phosphonomethoxy)propyl]uracil (1-4) have been synthesized together with the 1′ and 2′-ethynyl derivatives of 9/1-[2′-(phosphonomethoxy)ethyl]adenine/thymine (5-7). Key intermediates leading to the latter series are (±)-[2-{diethyl(phosphonomethoxy)}-1- hydroxy]-but-3-yne (25) and (±)-diisopropyl{[2-hydroxy-4-(trimethylsilyl) but-3-yn-1-yl]oxy}methylphosphonate (30). Compounds 25 and 30 are easily obtained starting from (±)-solketal. © 2011 Elsevier Ltd. All rights reserved.

Christ F.,Catholic University of Leuven | Voet A.,Laboratory for Biomolecular Modelling | Marchand A.,Center for Innovation and Stimulation of Medicines Development | Nicolet S.,Catholic University of Leuven | And 10 more authors.
Nature Chemical Biology | Year: 2010

Lens epitheliumĝ€"derived growth factor (LEDGF/p75) is a cellular cofactor of HIV-1 integrase that promotes viral integration by tethering the preintegration complex to the chromatin. By virtue of its crucial role in the early steps of HIV replication, the interaction between LEDGF/p75 and integrase represents an attractive target for antiviral therapy. We have rationally designed a series of 2-(quinolin-3-yl)acetic acid derivatives (LEDGINs) that act as potent inhibitors of the LEDGF/p75-integrase interaction and HIV-1 replication at submicromolar concentration by blocking the integration step. A 1.84-Å... resolution crystal structure corroborates the binding of the inhibitor in the LEDGF/p75-binding pocket of integrase. Together with the lack of cross-resistance with two clinical integrase inhibitors, these findings define the 2-(quinolin-3-yl)acetic acid derivatives as the first genuine allosteric HIV-1 integrase inhibitors. Our work demonstrates the feasibility of rational design of small molecules inhibiting the protein-protein interaction between a viral protein and a cellular host factor.

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