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Synthesis, stability, antiviral activity, and protease-bound structures of substrate-mimicking constrained macrocyclic inhibitors of HIV-1 protease

Journal Article


Abstract


  • Three new peptidomimetics (1-3) have been developed with highly stable and conformationally constrained macrocyclic components that replace tripeptide segments of protease substrates. Each compound inhibits both HIV-1 protease and viral replication (HIV-1, HIV-2) at nanomolar concentrations without cytotoxicity to uninfected cells below 10 μM. Their activities against HIV-1 protease (K(i) 1.7 nM (1), 0.6 nM (2), 0.3 nM (3)) are 1-2 orders of magnitude greater than their antiviral potencies against HIV-1-infected primary peripheral blood mononuclear cells (IC 50 45 nM (1), 56 nM (2), 95 nM (3)) or HIV-1-infected MT2 cells (IC 50 90 nM (1), 60 nM (2)), suggesting suboptimal cellular uptake. However their antiviral potencies are similar to those of indinavir and amprenavir under identical conditions. There were significant differences in their capacities to inhibit the replication of HIV-1 and HIV-2 in infected MT2 cells, 1 being ineffective against HIV-2 while 2 was equally effective against both virus types. Evidence is presented that 1 and 2 inhibit cleavage of the HIV-1 structural protein precursor P°r55(gag) to p24 in virions derived from chronically infected cells, consistent with inhibition of the viral protease in cells. Crystal structures refined to 1.75 Å (1) and 1.85 Å (2) for two of the macrocyclic inhibitors bound to HIV-1 protease establish structural mimicry of the tripeptides that the cycles were designed to imitate. Structural comparisons between protease-bound macrocyclic inhibitors, VX478 (amprenavir), and L-735,524 (indinavir) show that their common acyclic components share the same space in the active site of the enzyme and make identical interactions with enzyme residues. This substrate-mimicking minimalist approach to drug design could have benefits in the context of viral resistance, since mutations which induce inhibitor resistance may also be those which prevent substrate processing.

UOW Authors


  •   Tyndall, Joel (external author)
  •   Reid, Robert (external author)
  •   Tyssen, David (external author)
  •   Jardine, Darren (external author)
  •   Todd, Belinda (external author)
  •   Passmore, Malcolm S. (external author)
  •   March, Darren (external author)
  •   Pattenden, Leonard (external author)
  •   Bergman, Douglas (external author)
  •   Alewood, Dianne (external author)
  •   Hu, Shu-Hong (external author)
  •   Alewood, Paul F. (external author)
  •   Birch, Chrisopher J. (external author)
  •   Martin, Jennifer
  •   Fairlie, David P. (external author)

Publication Date


  • 2000

Citation


  • Tyndall, J. D. A., Reid, R. C., Tyssen, D. P., Jardine, D. K., Todd, B., Passmore, M., March, D. R., Pattenden, L. K., Bergman, D. A., Alewood, D., Hu, S., Alewood, P. F., Birch, C. J., Martin, J. L. & Fairlie, D. P. (2000). Synthesis, stability, antiviral activity, and protease-bound structures of substrate-mimicking constrained macrocyclic inhibitors of HIV-1 protease. Journal of Medicinal Chemistry, 43 (19), 3495-3504.

Scopus Eid


  • 2-s2.0-0034699496

Number Of Pages


  • 9

Start Page


  • 3495

End Page


  • 3504

Volume


  • 43

Issue


  • 19

Place Of Publication


  • United States

Abstract


  • Three new peptidomimetics (1-3) have been developed with highly stable and conformationally constrained macrocyclic components that replace tripeptide segments of protease substrates. Each compound inhibits both HIV-1 protease and viral replication (HIV-1, HIV-2) at nanomolar concentrations without cytotoxicity to uninfected cells below 10 μM. Their activities against HIV-1 protease (K(i) 1.7 nM (1), 0.6 nM (2), 0.3 nM (3)) are 1-2 orders of magnitude greater than their antiviral potencies against HIV-1-infected primary peripheral blood mononuclear cells (IC 50 45 nM (1), 56 nM (2), 95 nM (3)) or HIV-1-infected MT2 cells (IC 50 90 nM (1), 60 nM (2)), suggesting suboptimal cellular uptake. However their antiviral potencies are similar to those of indinavir and amprenavir under identical conditions. There were significant differences in their capacities to inhibit the replication of HIV-1 and HIV-2 in infected MT2 cells, 1 being ineffective against HIV-2 while 2 was equally effective against both virus types. Evidence is presented that 1 and 2 inhibit cleavage of the HIV-1 structural protein precursor P°r55(gag) to p24 in virions derived from chronically infected cells, consistent with inhibition of the viral protease in cells. Crystal structures refined to 1.75 Å (1) and 1.85 Å (2) for two of the macrocyclic inhibitors bound to HIV-1 protease establish structural mimicry of the tripeptides that the cycles were designed to imitate. Structural comparisons between protease-bound macrocyclic inhibitors, VX478 (amprenavir), and L-735,524 (indinavir) show that their common acyclic components share the same space in the active site of the enzyme and make identical interactions with enzyme residues. This substrate-mimicking minimalist approach to drug design could have benefits in the context of viral resistance, since mutations which induce inhibitor resistance may also be those which prevent substrate processing.

UOW Authors


  •   Tyndall, Joel (external author)
  •   Reid, Robert (external author)
  •   Tyssen, David (external author)
  •   Jardine, Darren (external author)
  •   Todd, Belinda (external author)
  •   Passmore, Malcolm S. (external author)
  •   March, Darren (external author)
  •   Pattenden, Leonard (external author)
  •   Bergman, Douglas (external author)
  •   Alewood, Dianne (external author)
  •   Hu, Shu-Hong (external author)
  •   Alewood, Paul F. (external author)
  •   Birch, Chrisopher J. (external author)
  •   Martin, Jennifer
  •   Fairlie, David P. (external author)

Publication Date


  • 2000

Citation


  • Tyndall, J. D. A., Reid, R. C., Tyssen, D. P., Jardine, D. K., Todd, B., Passmore, M., March, D. R., Pattenden, L. K., Bergman, D. A., Alewood, D., Hu, S., Alewood, P. F., Birch, C. J., Martin, J. L. & Fairlie, D. P. (2000). Synthesis, stability, antiviral activity, and protease-bound structures of substrate-mimicking constrained macrocyclic inhibitors of HIV-1 protease. Journal of Medicinal Chemistry, 43 (19), 3495-3504.

Scopus Eid


  • 2-s2.0-0034699496

Number Of Pages


  • 9

Start Page


  • 3495

End Page


  • 3504

Volume


  • 43

Issue


  • 19

Place Of Publication


  • United States