 |
PDBsum entry 1ztz
|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
From nonpeptide toward noncarbon protease inhibitors: metallacarboranes as specific and potent inhibitors of HIV protease.
|
|
|
Authors
|
|
P.Cígler,
M.Kozísek,
P.Rezácová,
J.Brynda,
Z.Otwinowski,
J.Pokorná,
J.Plesek,
B.Grüner,
L.Dolecková-Maresová,
M.Mása,
J.Sedlácek,
J.Bodem,
H.G.Kräusslich,
V.Král,
J.Konvalinka.
|
|
|
Ref.
|
|
Proc Natl Acad Sci U S A, 2005,
102,
15394-15399.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
HIV protease (PR) represents a prime target for rational drug design, and
protease inhibitors (PI) are powerful antiviral drugs. Most of the current PIs
are pseudopeptide compounds with limited bioavailability and stability, and
their use is compromised by high costs, side effects, and development of
resistant strains. In our search for novel PI structures, we have identified a
group of inorganic compounds, icosahedral metallacarboranes, as candidates for a
novel class of nonpeptidic PIs. Here, we report the potent, specific, and
selective competitive inhibition of HIV PR by substituted metallacarboranes. The
most active compound, sodium hydrogen butylimino
bis-8,8-[5-(3-oxa-pentoxy)-3-cobalt bis(1,2-dicarbollide)]di-ate, exhibited a
K(i) value of 2.2 nM and a submicromolar EC(50) in antiviral tests, showed no
toxicity in tissue culture, weakly inhibited human cathepsin D and pepsin, and
was inactive against trypsin, papain, and amylase. The structure of the parent
cobalt bis(1,2-dicarbollide) in complex with HIV PR was determined at 2.15 A
resolution by protein crystallography and represents the first carborane-protein
complex structure determined. It shows the following mode of PR inhibition: two
molecules of the parent compound bind to the hydrophobic pockets in the
flap-proximal region of the S3 and S3' subsites of PR. We suggest, therefore,
that these compounds block flap closure in addition to filling the corresponding
binding pockets as conventional PIs. This type of binding and inhibition,
chemical and biological stability, low toxicity, and the possibility to
introduce various modifications make boron clusters attractive pharmacophores
for potent and specific enzyme inhibition.
|
|
|
|
|
|
|
|
Figure 1.
Fig. 1. Ring opening reaction of 8-dioxane-3-cobalt
bis(1,2-dicarbollide) 7 by different nucleofiles Nu0 (e.g.,
NH[3]) and Nu- (e.g., RO-) yielding zwitterionic and anionic
compounds, respectively.
|
|
Figure 3.
Fig. 3. Interactions of compound 1 with the amino acid
residues in the corresponding PR-binding pocket. (A) Binding of
compound 1 molecule Cb1 by PR monomer A (red tube). (B) Binding
of compound 1 molecule Cb2 by PR monomer B (blue tube). Compound
1 is represented by a stick model in gray, with cobalt shown as
a magenta sphere. PR residues in contact with compound 1 are
represented by stick models, and their solvent-accessible
surfaces are colored by atom charge (blue, positive; red,
negative). (C) Superposition of the two compound 1-binding
modes. The color scheme and representation for PR is the same as
in A and B, and atoms in compound 1 are colored with the color
of the interacting PR chain.
|
|
|
|
|
|
|
|
|
|
