1D4L

HIV-1 PROTEASE COMPLEXED WITH A MACROCYCLIC PEPTIDOMIMETIC INHIBITOR

Summary for 1D4L

• Entry DOI: 10.2210/pdb1d4l/pdb
• Related: 1b6j 1b6l 1b6n 1b6o
• Descriptor: HIV-1 PROTEASE, SULFATE ION, (10S,13S,1'R)-13-[1'-HYDROXY-2'-(N-P-AMINOBENZENESULFONYL-1''-AMINO-3''-METHYLBUTYL)ETHYL]-8,11-DIOXO-10-ISOPROPYL-2-OXA-9,12-DIAZABICYCLO [13.2.2]NONADECA-15,17,18-TRIENE, ... (4 entities in total)
• Functional Keywords: hiv, protease, inhibitor, antiviral, hydrolase
• Cellular location: Gag-Pol polyprotein: Host cell membrane; Lipid-anchor. Matrix protein p17: Virion membrane; Lipid- anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P03369
• Total number of polymer chains: 2
• Total formula weight: 22436.38

Authors

Tyndall, J.D.,Reid, R.C.,Tyssen, D.P.,Jardine, D.K.,Todd, B.,Passmore, M.,March, D.R.,Pattenden, L.K.,Alewood, D.,Hu, S.H.,Alewood, P.F.,Birch, C.J.,Martin, J.L.,Fairlie, D.P. (deposition date: 1999-10-04, release date: 2000-10-11, Last modification date: 2021-11-03)

Primary citation

Tyndall, J.D.,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.H.,Alewood, P.F.,Birch, C.J.,Martin, J.L.,Fairlie, D.P.
Synthesis, stability, antiviral activity, and protease-bound structures of substrate-mimicking constrained macrocyclic inhibitors of HIV-1 protease.
J.Med.Chem., 43:3495-3504, 2000

PubMed 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 microM. 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 Pr55(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 A (1) and 1.85 A (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.

PubMed: 11000004
DOI: 10.1021/jm000013n

Experimental method

X-RAY DIFFRACTION (1.75 Å)