Biology Reference
In-Depth Information
Fig. 7.
Correlation between the cologarithm of the optical density (pOD) deter-
mined experimentally by ELISA for a series of rationally designed TCR mutants
(Melita B. Irving, private communication) and the binding free energy change upon
the corresponding mutation (
G
bind
) calculated using the MM-GBSA approach.
Higher-affinity mutants are characterized by low pOD and negative
∆∆
∆∆
G
bind
values.
The circle corresponds to the wild-type TCR.
immune tolerance by tumors. IDO catalyzes the initial and rate-limiting
step in the catabolism of tryptophan (Trp) along the kynurenine
pathway.
64
By depleting Trp locally, IDO blocks the proliferation of
T lymphocytes, which are extremely sensitive to Trp shortage. The
observation that many human tumors constitutively express IDO intro-
duced the hypothesis that its inhibition could enhance the effectiveness
of cancer immunotherapy. Results from
in vitro
and
in vivo
studies
suggest that the efficacy of therapeutic vaccination of cancer patients
may indeed be improved by concomitant administration of an IDO
inhibitor.
65,66
Most known IDO inhibitors display affinities in the micromolar range,
but recently some submicromolar inhibitors have been discovered.
67-69
The crystal structures of human IDO
70
complexed with 4-phenylimidazole
(PIM) can serve as a scaffold for the
in silico
design of new and more
potent IDO inhibitors.
