Exploring the role of the α-carboxyphosphonate moiety in the HIV-RT activity of α-carboxy nucleoside phosphonates

Organic & Biomolecular Chemistry
Nicholas D MullinsAnita R Maguire

Abstract

As α-carboxy nucleoside phosphonates (α-CNPs) have demonstrated a novel mode of action of HIV-1 reverse transcriptase inhibition, structurally related derivatives were synthesized, namely the malonate 2, the unsaturated and saturated bisphosphonates 3 and 4, respectively and the amide 5. These compounds were evaluated for inhibition of HIV-1 reverse transcriptase in cell-free assays. The importance of the α-carboxy phosphonoacetic acid moiety for achieving reverse transcriptase inhibition, without the need for prior phosphorylation, was confirmed. The malonate derivative 2 was less active by two orders of magnitude than the original α-CNPs, while displaying the same pattern of kinetic behavior; interestingly the activity resides in the “L”-enantiomer of 2, as seen with the earlier series of α-CNPs. A crystal structure with an RT/DNA complex at 2.95 Å resolution revealed the binding of the “L”-enantiomer of 2, at the polymerase active site with a weaker metal ion chelation environment compared to 1a (T-α-CNP) which may explain the lower inhibitory activity of 2.

References

May 9, 2002·Proceedings of the National Academy of Sciences of the United States of America·Jay A GroblerDaria J Hazuda
Jul 12, 2002·Journal of Medicinal Chemistry·Godwin C G PaisTerrence R Burke
Dec 14, 2002·The Journal of Biological Chemistry·Cathryn A Shaw-ReidDaria J Hazuda
Mar 19, 2003·Bioorganic Chemistry·Charles E McKennaChristian N Rozé
Jun 25, 2004·Journal of Medicinal Chemistry·Elena A ShirokovaAndrey G Pokrovsky
Nov 17, 2006·Expert Opinion on Investigational Drugs·Andrea Savarino
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsPeter H Zwart
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·P EmsleyK Cowtan
Dec 3, 2010·The Journal of Organic Chemistry·Sebastien DebargeAnita R Maguire
May 3, 2011·Journal of Molecular Graphics & Modelling·Meilan HuangW Graham Richards
Aug 22, 2014·Journal of Medicinal Chemistry·Cyrus M LacbayYoula S Tsantrizos
Nov 27, 2014·Endocrine·Fabio Vescini, Franco Grimaldi
Dec 3, 2014·Proceedings of the National Academy of Sciences of the United States of America·Rebecca PaynePhilip J R Goulder
Mar 4, 2015·Proceedings of the National Academy of Sciences of the United States of America·Jan BalzariniEddy Arnold
Aug 25, 2015·Protein Science : a Publication of the Protein Society·Matthew T MillerEddy Arnold
Oct 2, 2015·The Lancet. HIV·Nikos PantazisUNKNOWN CASCADE Collaboration in EuroCoord

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Citations

Jun 24, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Olga A KhomichSergey N Kochetkov
Dec 3, 2016·Nucleic Acids Research·Andrea PicaFilomena Sica
Jan 17, 2019·Future Medicinal Chemistry·Jan BalzariniAnita Maguire
Jul 11, 2020·Beilstein Journal of Organic Chemistry·Katarzyna JustynaKatarzyna M Błażewska
Oct 12, 2019·Journal of Medicinal Chemistry·F Xavier RuizEddy Arnold

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