Modular construction of quaternary hemiaminal-based inhibitor candidates and their in cellulo assessment with HIV-1 protease

Guillaume Gros; Lorena Martinez; Anna Servat Gimenez; Paula Adler; Philippe Maurin; Roland Wolkowicz; Pierre Falson; Jens Hasserodt

doi:10.1016/j.bmc.2013.06.018

Modular construction of quaternary hemiaminal-based inhibitor candidates and their in cellulo assessment with HIV-1 protease

Bioorg Med Chem. 2013 Sep 1;21(17):5407-13. doi: 10.1016/j.bmc.2013.06.018. Epub 2013 Jun 14.

Authors

Guillaume Gros¹, Lorena Martinez, Anna Servat Gimenez, Paula Adler, Philippe Maurin, Roland Wolkowicz, Pierre Falson, Jens Hasserodt

Affiliation

¹ Laboratoire de Chimie, Université de Lyon - ENS, 46 allée d'Italie, 69364 Lyon, France.

PMID: 23911197
DOI: 10.1016/j.bmc.2013.06.018

Abstract

Non-peptidomimetic drug-like protease inhibitors have potential for circumventing drug resistance. We developed a much-improved synthetic route to our previously reported inhibitor candidate displaying an unusual quaternized hemi-aminal. This functional group forms from a linear precursor upon passage into physiological media. Seven variants were prepared and tested in cellulo with our HIV-1 fusion-protein technology that result in an eGFP-based fluorescent readout. Three candidates showed inhibition potency above 20μM and toxicity at higher concentrations, making them attractive targets for further refinement. Importantly, our class of original inhibitor candidates is not recognized by two major multidrug resistance pumps, quite in contrast to most clinically applied HIV-1 protease inhibitors.

Keywords: Antiviral agents; Cellular assay; Chemical synthesis; Cyclic urea; HIV-1 protease inhibitors; Quaternary hemiaminal; Transition-state isostere.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
ATP Binding Cassette Transporter, Subfamily G, Member 2
ATP-Binding Cassette Transporters / genetics
ATP-Binding Cassette Transporters / metabolism
Animals
Cell Line
Cell Survival / drug effects
HEK293 Cells
HIV Protease / chemistry*
HIV Protease / metabolism
HIV Protease Inhibitors / chemical synthesis
HIV Protease Inhibitors / chemistry*
HIV Protease Inhibitors / toxicity
HIV-1 / enzymology*
Humans
Mice
NIH 3T3 Cells
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism
Urea / chemical synthesis
Urea / chemistry
Urea / toxicity

Substances

ABCG2 protein, human
ATP Binding Cassette Transporter, Subfamily B, Member 1
ATP Binding Cassette Transporter, Subfamily G, Member 2
ATP-Binding Cassette Transporters
HIV Protease Inhibitors
Neoplasm Proteins
Urea
HIV Protease
p16 protease, Human immunodeficiency virus 1