 |
PDBsum entry 2o4l
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Viral protein
|
PDB id
|
|
|
|
2o4l
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Unique thermodynamic response of tipranavir to human immunodeficiency virus type 1 protease drug resistance mutations.
|
|
|
Authors
|
|
S.Muzammil,
A.A.Armstrong,
L.W.Kang,
A.Jakalian,
P.R.Bonneau,
V.Schmelmer,
L.M.Amzel,
E.Freire.
|
|
|
Ref.
|
|
J Virol, 2007,
81,
5144-5154.
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Drug resistance is a major problem affecting the clinical efficacy of
antiretroviral agents, including protease inhibitors, in the treatment of
infection with human immunodeficiency virus type 1 (HIV-1)/AIDS. Consequently,
the elucidation of the mechanisms by which HIV-1 protease inhibitors maintain
antiviral activity in the presence of mutations is critical to the development
of superior inhibitors. Tipranavir, a nonpeptidic HIV-1 protease inhibitor, has
been recently approved for the treatment of HIV infection. Tipranavir inhibits
wild-type protease with high potency (K(i) = 19 pM) and demonstrates durable
efficacy in the treatment of patients infected with HIV-1 strains containing
multiple common mutations associated with resistance. The high potency of
tipranavir results from a very large favorable entropy change (-TDeltaS = -14.6
kcal/mol) combined with a favorable, albeit small, enthalpy change (DeltaH =
-0.7 kcal/mol, 25 degrees C). Characterization of tipranavir binding to
wild-type protease, active site mutants I50V and V82F/I84V, the
multidrug-resistant mutant L10I/L33I/M46I/I54V/L63I/V82A/I84V/L90M, and the
tipranavir in vitro-selected mutant I13V/V32L/L33F/K45I/V82L/I84V was performed
by isothermal titration calorimetry and crystallography. Thermodynamically, the
good response of tipranavir arises from a unique behavior: it compensates for
entropic losses by actual enthalpic gains or by sustaining minimal enthalpic
losses when facing the mutants. The net result is a small loss in binding
affinity. Structurally, tipranavir establishes a very strong hydrogen bond
network with invariant regions of the protease, which is maintained with the
mutants, including catalytic Asp25 and the backbone of Asp29, Asp30, Gly48 and
Ile50. Moreover, tipranavir forms hydrogen bonds directly to Ile50, while all
other inhibitors do so by being mediated by a water molecule.
|
|
|
|
|
|
|
