title: Modular construction of quaternary hemiaminal-based inhibitor candidates and their in cellulo assessment with HIV-1 protease.
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.
authors.affiliation: Laboratoire de Chimie, Université de Lyon - ENS, 46 allée d'Italie, 69364 Lyon, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Gros
authors.forename: Lorena
authors.initials: L
authors.lastname: Martinez
authors.forename: Anna Servat
authors.initials: AS
authors.lastname: Gimenez
authors.forename: Paula
authors.initials: P
authors.lastname: Adler
authors.forename: Philippe
authors.initials: P
authors.lastname: Maurin
authors.forename: Roland
authors.initials: R
authors.lastname: Wolkowicz
authors.forename: Pierre
authors.initials: P
authors.lastname: Falson
authors.forename: Jens
authors.initials: J
authors.lastname: Hasserodt
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D057809:HEK293 Cells; D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D014508:Urea / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity
chemical_list: C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D017320:HIV Protease Inhibitors; D009363:Neoplasm Proteins; D014508:Urea; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1
keywords: Antiviral agents; Cellular assay; Chemical synthesis; Cyclic urea; HIV-1 protease inhibitors; Quaternary hemiaminal; Transition-state isostere