TMC310911, a novel human immunodeficiency virus type 1 protease inhibitor, shows in vitro an improved resistance profile and higher genetic barrier to resistance compared with current protease inhibitors

Abstract

TMC310911 is a novel human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) structurally closely related to darunavir (DRV) but with improved virological characteristics. TMC310911 has potent activity against wild-type (WT) HIV-1 (median 50% effective concentration [EC(50)], 14 nM) and a wide spectrum of recombinant HIV-1 clinical isolates, including multiple-PI-resistant strains with decreased susceptibility to currently approved PIs (fold change [FC] in EC(50), >10). For a panel of 2,011 recombinant clinical isolates with decreased susceptibility to at least one of the currently approved PIs, the FC in TMC310911 EC(50) was ≤ 4 for 82% of isolates and ≤ 10 for 96% of isolates. The FC in TMC310911 EC(50) was ≤ 4 and ≤ 10 for 72% and 94% of isolates with decreased susceptibility to DRV, respectively. In vitro resistance selection (IVRS) experiments with WT virus and TMC310911 selected for mutations R41G or R41E, but selection of resistant virus required a longer time than IVRS performed with WT virus and DRV. IVRS performed with r13025, a multiple-PI-resistant recombinant clinical isolate, and TMC310911 selected for mutations L10F, I47V, and L90M (FC in TMC310911 EC(50) = 16). IVRS performed with r13025 in the presence of DRV required less time and resulted in more PI resistance-associated mutations (V32I, I50V, G73S, L76V, and V82I; FC in DRV EC(50) = 258). The activity against a comprehensive panel of PI-resistant mutants and the limited in vitro selection of resistant viruses under drug pressure suggest that TMC310911 represents a potential drug candidate for the management of HIV-1 infection for a broad range of patients, including those with multiple PI resistance.

Figures

Fig. 1.

Structures of (A) TMC310911 and (B) darunavir.

Fig. 2.

Activity of different PIs against a series (n = 2,011) of recombinant clinical isolates with various levels of genotypic diversity and phenotypic susceptibility and an EC50 FC > 10 for at least 1 of the currently approved PIs (APV, ATV, DRV, IDV, LPV, SQV and TPV). Antivirogram clinical cutoff (CCO): DRV FC = 10, LPV FC = 10, TPV FC = 3. Antivirogram biological cutoff (BCO): APV FC = 2.2, ATV FC = 2.1, IDV FC = 2.3, SQV FC = 1.8.

Fig. 3.

Comparison of the activity of TMC310911 against DRV (A) and TPV (B) determined with a series of recombinant clinical isolates (n = 2,781 [A] and 2,427 [B]) with various levels of genotypic diversity and phenotypic susceptibility (censored values are not shown). The Antivirogram clinical cutoff (CCO) for DRV (FC = 10) and TPV (FC = 3) are represented by horizontal lines; the TMC310911 FC value of 4 is represented by vertical lines.

Fig. 4.

Activity (FC in EC50) against a series of recombinant clinical isolates with various levels of genotypic diversity and phenotypic susceptibility (censored values not shown) according to the number of (A) major PI RAMs for TMC310911, DRV, LPV and TPV (n = 1,388) and (B) DRV RAMs for TMC310911 and DRV (n = 2,781). Each box plot depicts the median value (horizontal lines), lower (Q1) and upper (Q3) quartile (squared bar), upper (largest value ≤ Q3 + 1.5 IQR) and lower (lowest value ≥ Q1 − 1.5 IQR) adjacent values (vertical lines), and outlier values (dots). The Antivirogram clinical cutoff (CCO) values for DRV and LPV (FC = 10) and TPV (FC = 3) and the FC value of 4 for TMC310911 are represented by horizontal lines. DRV RAMs: V11I, V32I, L33F, I47V, I50V, I54L/M, T74P, L76V, I84V, and L89V (12). Major PI RAMs: D30N, V32I, M46I/L, I47A/V, G48V, I50L/V, I54L/M, Q58E, T74P, L76V, V82A/F/L/S/T, I84V, N88S, and L90M (12).

Fig. 5.

In vitro selection of resistant HIV-1 starting from WT HIV-1/LAI in the presence of TMC310911 or DRV. Selection curves have been normalized, and starting selection concentrations were 20 and 10 nM for TMC310911 and DRV, respectively. Genotypes of virus strains selected at defined time points (indicated by filled symbols) list all changes from the starting strain HIV-1/LAI.

Fig. 6.

In vitro selection of resistant HIV-1 starting from r13025, a PI-resistant recombinant clinical isolate, in the presence of TMC310911 or DRV. Selection curves have been normalized, and the starting selection concentration was 20 nM for TMC310911 and DRV. Genotypes of virus strains selected at defined time points (indicated by filled symbols) list the mutations that developed in the protease compared to the starting r13025 strain, which already contained 7 PI RAMs.

Fig. 7.

The hydrogen bond network formed between TMC310911 and the WT HIV-1 protease. The hydrogen bonds formed by one conformation of TMC310911 are shown here. A second conformation resulted in a similar hydrogen-bonding network. The piperidine and cyclopentyl rings are not well ordered in either conformation.