immunodeficiency virus type 1 (HIV-1) protease (PR) is a retroviral aspartyl protease with an essential role in the final step of viral maturation. the high drug selection pressure and extremely error-prone viral reverse transcriptase that lacks the proofreading step.8 9 Among the clinical PIs darunavir (DRV) exerts high antiviral activity against a wide Dihydroartemisinin spectrum of HIV-1 variants10 11 with the enzyme inhibitory potency in the low picomolar range (Ki = 16 pM).12 DRV is a second generation PI that utilized the “backbone binding” strategy to Dihydroartemisinin maximize the interaction between inhibitor and PR backbone atoms.13 The recently described nonpeptidic PI GRL-02031 (1) (Figure 1A) based on the DRV scaffold retains potent activity against laboratory and primary HIV-1 strains.14 Compound 1 offers additional benefits over other clinical PIs with its low dose cytotoxicity (CC50 >100 μM) and Ile47 shows a strong association with decreased susceptibility to amprenavir (APV) darunavir (DRV) lopinavir (LPV) and tipranavir (TPV).19 21 Similarly L76V mutation shows decreased susceptibility for APV DRV and LPV. Interestingly this mutation has an opposing effect on other drugs as it becomes hypersensitive to atazanavir (ATV) saquinavir (SQV) and Mouse monoclonal to HAUSP TPV.22 23 Mutations of V82A/T/F/S/L are very (+)-MK 801 Maleate common in PI resistance and show reduced susceptibility to all the clinical PIs except DRV.