U-90152, a potent inhibitor of human immunodeficiency virus type 1 replication

Abstract

Bisheteroarylpiperazines are potent inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). We describe a novel bisheteroarylpiperazine, U-90152 {1-(5-methanesulfonamido-IH-indol-2-yI-carbonyl)-4-[3-(1-methylethyl-amino)pyridinyllpiperazine}, which inhibited recombinant HIV-1 RT at a 50%Y inhibitory concentration (IC.) of 0.26 FLM (compared with IC50s of >440 ,uM for DNA polymerases at and B). U-90152 blocked the replication in peripheral blood lymphocytes of 25 primary HWV-i isolates, including variants that were highly resistant to 3'-azido-2',3'-dideoxythymidine (AZT) or 2',3'-dideoxyinosine, with a mean 50%o effective dose of 0.066 + 0.137 pM. U-90152 had low cellular cytotoxicity, causing less than 8% reduction in peripheral blood lymphocyte viability at 100 ,uM. In experiments assessing inhibition of the spread of HIV-MB in cell cultures, U-90152 was much more effective than AZT. When approximately 500 HIV-1l1m-infected MT-4 cells were mixed 1:1,000 with uninfected cells, 3 ,uM AZT delayed the evidence of rapid viral growth for 7 days. In contrast, 3 ,uM U-90152 totally prevented the spread of HIV-i, and death and/or dilution of the original inoculum of infected cells prevented renewed viral growth after U-90152 was removed at day 24. The combination of U-90152 and AZT, each at 0.5 ,uM, also totally prevented viral spread. Finally, although the RT amino acid substitutions K103N (lysine 103 to asparagine) and Y181C (tyrosine 181 to cysteine), which confer cross-resistance to several nonnucleoside inhibitors, also decrease the potency of U-90152, this drug retains significant activity against these mutant RTs in vitro (IC50s, approximately 8 ,uM).

Mechanism of resistance to U‐90152S and sensitization to L‐697,661 by a proline to leucine change at residue 236 of human immunodeficiency virus type 1 (HIV‐1) reverse transcriptase

“…3). This direct correlation between sensitization to L-697,661 and resistance to U-90152S supports the previous evidence [20,21] that these structurally dissimilar RT inhibitors share the same binding pocket [10].…”

“…When HIV-1 was grown in the presence of L-697,661, viral variants were resistant to all these three classes of nonnucleosides [15]. These [14,15] and other studies [1,7,[16][17][18][19][20][21] suggest that most classes of NNRTIs appear to share the same binding pocket on the enzyme [10].…”

Simultaneous mutations at Tyr‐181 and Tyr‐188 in HIV‐1 reverse transcriptase prevents inhibition of RNA‐dependent DNA polymerase activity by the bisheteroarylpiperazine (BHAP) U‐90152s

“…It is believed that insensitivity of HIV-2 RT to these NNRTIs is primarily due to the presence of Ile-181 or Leu-188 [17,[20][21][22]. Subsequently, there were differences in the pattern of resistance mutations observed in the presence of NNRTIs [11,[23][24][25][26][27]. Taken together, these studies suggest that there is a common binding pocket [16] and overlapping binding sites for different inhibitors.…”

“…2) distinguishes it from the other well known classes of NNRTIs [20][21][22]26]. The BHAP U-90152S is also active versus the Y181C HIV-1 RT mutant and selects for a P236L resistance mutation in cell culture experiments [25]. These characteristics of U-90152S are not shared by TIBO R82913, nevirapine, and L-697,661.…”

Pyrido [1,2a] Indole Derivatives Identified as Novel Nonnucleoside Reverse Transcriptase Inhibitors of Human Immunodeficiency Virus Type 1

“…These compounds have no antiviral activity against HIV-2 and are targeted at a non-substrate binding site of the HIV-1 RT (Cohen et al, 1991;Dueweke et al, 1992;Esnouf et al, 1995;Das et al, 1996). Among this type of compound, nevirapine (Boehringer Ingelheim; BI-RG-587) (Carr et al, 1996), delavirdine (Pharmacia & Upjohn; BHAP, U90152T) (Dueweke et al, 1993), atevirdine (Pharmacia & Upjohn; BHAP, U-87201E) (Reichman et al, 1995), loviride ( Janssen; R89439, α-APA) (Staszewski et al, 1996) and 726) (Young et al, 1995) Richman et al, 1991). This means the clinical benefit is short-lived.…”