| Human immunodefeciency virus type1(HIV-1) is the etiologic agent responsible for the onset of the acquired immunodeficiency syndrome (AIDS). AIDS has killed more than30million people since it was first defined in the year1982as the manifestation of a deficiency in the human immune system. It is one of the most destructive epidemics in recorded history.The human immunodeficiency virus belongs to the lentivirus family of retroviruses. The singlestranded RNA genome is packaged inside a protein core particle and surrounded by a lipid envelope, in which is embedded the outer coat (envelope) protein, GP120. Infection of the T-helper (CD4+) lymphocytes and monocytes begins through the adsorption of virons to the cell surface mediated by the specific interaction of the virus envelope protein with CD4molecules on the cell surface. After the viral entrance, the virus uncoats and the duplicate single-stranded RNA genome is reversely transcribed into a double-stranded DNA genome by the viral enzyme reverse transcriptase (RT). Integration into the host DNA is followed by transcription and translation of HIV-1genes. The viral capsid and RT, encoded by the gag and pol genes, respectively are expressed initially as large polypeptideprecursors. Although the precursor protein can assemble into a virus particle, maturation of these newly formed particles into infectious virons requires the proteolytic cleavage of the precursor proteins. This processing is carried out by the virally encoded enzyme HIV-1protease.In the past27years, structure-based drug design has led to the discovery of ten FDA-approved PIs and several others in advanced clinical trials. However, the rapid emergence of drug-resistant HIV-1strains and the appearance of cross-resistance are severely limiting the long-term treatment options. Thus, numerous efforts have been made in the design and synthesis of novel protease inhibitors with broad-spectrum activity against multidrug-resistant HIV-1variants by medicinal chemists.Replacing the P2bis-THF moiety by a stereochemically defined trans-4-hydroxy-L-prolinamide, Liu’s group designed a series of protease inhibitors based on the (R)-(hydroxyethylamino)sulfonamide isostere, the core scaffold of darunavir. In the HIV-1protease inhibitory activity bioassay, the most potent compound has an IC50of16.6nM.Considering that natural trans-4-hydroxy-L-proline or isosorbide moiety can act as H-bond donor and H-bond receptor, and with the expection that these moieties can form multiple interactions with the enzyme "backbone", we designed a series of novel P2/P2’modified protease inhibitors based on the core scaffold of darunavir. The synthesized compounds have been tested for HIV-1protease inhibitory activity. All the compounds are very potent HIV-1protease inhibitors with IC50values in the nanomolar or subnanomolar ranges (0.05～8.50nM). With the exception of compound QX04(IC50=8.50nM), all the other ten compounds exhibiting very strong protease inhibitory activity (ICso=0.05～1.50nM), are more potent than drug Darunavir (3.8nM). Among them, compound QX08is the best and has an excellent IC50of0.05nM. Compounds QX06, QX07and QX09are also very potent HIV-1protease inhibitors with IC50values in the subnanomole ranges (-0.10nM). In general, when the compounds have the same P2ligands, the p-methoxyphenylsulfonamide analogs (e.g. QX01, IC50=1.28nM) are slightly more active than the p-aminobenzenesulfonamide analogs (e.g. QX04, IC50=8.5nM), while the compounds have the same P2’ligands, those with isosorbide moities (e.g. QX09, IC50=0.12nM) exhibit a little better inhibitory activity than those of trans-4-hydroxy-L-proline moieties (e.g. QX05, IC50=1.5nM).In summary, we have discovered very potent HIV-1protease inhibitors through rational drug design, using the trans-4-hydroxy-L-proline or isosorbide moiety as the P2ligands, based on the the "backbone binding" concept. It is expected to find more potent and less toxic HIV-1protease inhibitors through further structural modification in the future. |
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