16 research outputs found
Unique structure of ozoralizumab, a trivalent anti-TNFα NANOBODY® compound, offers the potential advantage of mitigating the risk of immune complex-induced inflammation
Biologics have become an important component of treatment strategies for a variety of diseases, but the immunogenicity of large immune complexes (ICs) and aggregates of biologics may increase risk of adverse events is a concern for biologics and it remains unclear whether large ICs consisting of intrinsic antigen and therapeutic antibodies are actually involved in acute local inflammation such as injection site reaction (ISR). Ozoralizumab is a trivalent, bispecific NANOBODY® compound that differs structurally from IgGs. Treatment with ozoralizumab has been shown to provide beneficial effects in the treatment of rheumatoid arthritis (RA) comparable to those obtained with other TNFα inhibitors. Very few ISRs (2%) have been reported after ozoralizumab administration, and the drug has been shown to have acceptable safety and tolerability. In this study, in order to elucidate the mechanism underlying the reduced incidence of ISRs associated with ozoralizumab administration, we investigated the stoichiometry of two TNFα inhibitors (ozoralizumab and adalimumab, an anti-TNFα IgG) ICs and the induction by these drugs of Fcγ receptor (FcγR)-mediated immune responses on neutrophils. Ozoralizumab-TNFα ICs are smaller than adalimumab-TNFα ICs and lack an Fc portion, thus mitigating FcγR-mediated immune responses on neutrophils. We also developed a model of anti-TNFα antibody-TNFα IC-induced subcutaneous inflammation and found that ozoralizumab-TNFα ICs do not induce any significant inflammation at injection sites. The results of our studies suggest that ozoralizumab is a promising candidate for the treatment of RA that entails a lower risk of the IC-mediated immune cell activation that leads to unwanted immune responses
Binding Free-Energy Calculation Is a Powerful Tool for Drug Optimization: Calculation and Measurement of Binding Free Energy for 7‑Azaindole Derivatives to Glycogen Synthase Kinase-3β
Present
computational lead (drug)-optimization is lacking in thermodynamic
tactics. To examine whether calculation of binding free-energy change
(Δ<i>G</i>) is effective for the lead-optimization
process, binding Δ<i>G</i>s of 7-azaindole derivatives
to the ATP binding site of glycogen synthase kinase-3β (GSK-3β)
were calculated. The result was a significant correlation coefficient
of <i>r</i> = 0.895 between calculated and observed Δ<i>G</i>s. This indicates that calculated Δ<i>G</i> reflects the inhibitory activities of 7-azaindole derivatives. In
addition to quantitative estimation of activity, Δ<i>G</i> calculation characterizes the thermodynamic behavior of 7-azaindole
derivatives, providing also useful information for inhibitor optimization
on affinity to water molecules
Discovery of Highly Potent and Selective Matrix Metalloproteinase‑7 Inhibitors by Hybridizing the S1′ Subsite Binder with Short Peptides
Matrix metalloproteinase-7 (MMP-7) has emerged as a protein
playing
important roles in both physiological and pathophysiological processes.
Despite the growing interest in MMP-7 as a potential therapeutic target
for diseases including cancer and fibrosis, potent and selective MMP-7
inhibitors have yet to be identified. Compound 1, previously
reported by Edman and co-workers, binds to the S1′ subsite
of MMP-7, exhibiting moderate inhibitory activity and selectivity.
To achieve both higher inhibitory activity and selectivity, we conceived
hybridizing 1 with short peptides. The initially designed
compound 6, which was a hybrid molecule between 1 and a tripeptide (Ala-Leu-Met) derived from an MMP-2-inhibitory
peptide (APP-IP), showed enhanced MMP-7-inhibitory activity. Subsequent
optimization of the peptide moiety led to the development of compound 18 with remarkable potency for MMP-7 and selectivity over
other MMP subtypes
Discovery of Highly Potent and Selective Matrix Metalloproteinase‑7 Inhibitors by Hybridizing the S1′ Subsite Binder with Short Peptides
Matrix metalloproteinase-7 (MMP-7) has emerged as a protein
playing
important roles in both physiological and pathophysiological processes.
Despite the growing interest in MMP-7 as a potential therapeutic target
for diseases including cancer and fibrosis, potent and selective MMP-7
inhibitors have yet to be identified. Compound 1, previously
reported by Edman and co-workers, binds to the S1′ subsite
of MMP-7, exhibiting moderate inhibitory activity and selectivity.
To achieve both higher inhibitory activity and selectivity, we conceived
hybridizing 1 with short peptides. The initially designed
compound 6, which was a hybrid molecule between 1 and a tripeptide (Ala-Leu-Met) derived from an MMP-2-inhibitory
peptide (APP-IP), showed enhanced MMP-7-inhibitory activity. Subsequent
optimization of the peptide moiety led to the development of compound 18 with remarkable potency for MMP-7 and selectivity over
other MMP subtypes
Discovery of Highly Potent and Selective Matrix Metalloproteinase‑7 Inhibitors by Hybridizing the S1′ Subsite Binder with Short Peptides
Matrix metalloproteinase-7 (MMP-7) has emerged as a protein
playing
important roles in both physiological and pathophysiological processes.
Despite the growing interest in MMP-7 as a potential therapeutic target
for diseases including cancer and fibrosis, potent and selective MMP-7
inhibitors have yet to be identified. Compound 1, previously
reported by Edman and co-workers, binds to the S1′ subsite
of MMP-7, exhibiting moderate inhibitory activity and selectivity.
To achieve both higher inhibitory activity and selectivity, we conceived
hybridizing 1 with short peptides. The initially designed
compound 6, which was a hybrid molecule between 1 and a tripeptide (Ala-Leu-Met) derived from an MMP-2-inhibitory
peptide (APP-IP), showed enhanced MMP-7-inhibitory activity. Subsequent
optimization of the peptide moiety led to the development of compound 18 with remarkable potency for MMP-7 and selectivity over
other MMP subtypes
Discovery of Highly Potent and Selective Matrix Metalloproteinase‑7 Inhibitors by Hybridizing the S1′ Subsite Binder with Short Peptides
Matrix metalloproteinase-7 (MMP-7) has emerged as a protein
playing
important roles in both physiological and pathophysiological processes.
Despite the growing interest in MMP-7 as a potential therapeutic target
for diseases including cancer and fibrosis, potent and selective MMP-7
inhibitors have yet to be identified. Compound 1, previously
reported by Edman and co-workers, binds to the S1′ subsite
of MMP-7, exhibiting moderate inhibitory activity and selectivity.
To achieve both higher inhibitory activity and selectivity, we conceived
hybridizing 1 with short peptides. The initially designed
compound 6, which was a hybrid molecule between 1 and a tripeptide (Ala-Leu-Met) derived from an MMP-2-inhibitory
peptide (APP-IP), showed enhanced MMP-7-inhibitory activity. Subsequent
optimization of the peptide moiety led to the development of compound 18 with remarkable potency for MMP-7 and selectivity over
other MMP subtypes
Discovery of TP0597850: A Selective, Chemically Stable, and Slow Tight-Binding Matrix Metalloproteinase‑2 Inhibitor with a Phenylbenzamide–Pentapeptide Hybrid Scaffold
Matrix metalloproteinase-2 (MMP2) is a zinc-dependent
endopeptidase
and a promising target for various diseases, including cancer and
fibrosis. Herein, we report the discovery of a novel MMP2-selective
inhibitor with high chemical stability and slow tight-binding features.
Based on the degradation mechanism of our small-molecule–peptide
hybrid 1, the tripeptide linker {5-aminopentanoic acid
[Ape(5)]–Glu–Asp} of 1 was replaced by
a shorter linker (γ-D-Glu). Phenylbenzamide was suitable for
the new generation of MMP2 inhibitors as an S1′ pocket-binding
group. The introduction of (4S)-aminoproline dramatically
increased the chemical stability while maintaining high subtype selectivity
because of its interaction with Glu130. TP0597850 (18) exhibited high stability over a wide range of pH values as well
as potent MMP2 inhibition (Ki = 0.034
nM) and ≥2000-fold selectivity determined using the inhibition
constants. A kinetic analysis revealed that it possesses slow tight-binding
nature with a long MMP2 dissociative half-life (t1/2 = 265 min)
Discovery of Highly Potent and Selective Matrix Metalloproteinase‑7 Inhibitors by Hybridizing the S1′ Subsite Binder with Short Peptides
Matrix metalloproteinase-7 (MMP-7) has emerged as a protein
playing
important roles in both physiological and pathophysiological processes.
Despite the growing interest in MMP-7 as a potential therapeutic target
for diseases including cancer and fibrosis, potent and selective MMP-7
inhibitors have yet to be identified. Compound 1, previously
reported by Edman and co-workers, binds to the S1′ subsite
of MMP-7, exhibiting moderate inhibitory activity and selectivity.
To achieve both higher inhibitory activity and selectivity, we conceived
hybridizing 1 with short peptides. The initially designed
compound 6, which was a hybrid molecule between 1 and a tripeptide (Ala-Leu-Met) derived from an MMP-2-inhibitory
peptide (APP-IP), showed enhanced MMP-7-inhibitory activity. Subsequent
optimization of the peptide moiety led to the development of compound 18 with remarkable potency for MMP-7 and selectivity over
other MMP subtypes
Discovery of TP0597850: A Selective, Chemically Stable, and Slow Tight-Binding Matrix Metalloproteinase‑2 Inhibitor with a Phenylbenzamide–Pentapeptide Hybrid Scaffold
Matrix metalloproteinase-2 (MMP2) is a zinc-dependent
endopeptidase
and a promising target for various diseases, including cancer and
fibrosis. Herein, we report the discovery of a novel MMP2-selective
inhibitor with high chemical stability and slow tight-binding features.
Based on the degradation mechanism of our small-molecule–peptide
hybrid 1, the tripeptide linker {5-aminopentanoic acid
[Ape(5)]–Glu–Asp} of 1 was replaced by
a shorter linker (γ-D-Glu). Phenylbenzamide was suitable for
the new generation of MMP2 inhibitors as an S1′ pocket-binding
group. The introduction of (4S)-aminoproline dramatically
increased the chemical stability while maintaining high subtype selectivity
because of its interaction with Glu130. TP0597850 (18) exhibited high stability over a wide range of pH values as well
as potent MMP2 inhibition (Ki = 0.034
nM) and ≥2000-fold selectivity determined using the inhibition
constants. A kinetic analysis revealed that it possesses slow tight-binding
nature with a long MMP2 dissociative half-life (t1/2 = 265 min)
Discovery of Highly Potent and Selective Matrix Metalloproteinase‑7 Inhibitors by Hybridizing the S1′ Subsite Binder with Short Peptides
Matrix metalloproteinase-7 (MMP-7) has emerged as a protein
playing
important roles in both physiological and pathophysiological processes.
Despite the growing interest in MMP-7 as a potential therapeutic target
for diseases including cancer and fibrosis, potent and selective MMP-7
inhibitors have yet to be identified. Compound 1, previously
reported by Edman and co-workers, binds to the S1′ subsite
of MMP-7, exhibiting moderate inhibitory activity and selectivity.
To achieve both higher inhibitory activity and selectivity, we conceived
hybridizing 1 with short peptides. The initially designed
compound 6, which was a hybrid molecule between 1 and a tripeptide (Ala-Leu-Met) derived from an MMP-2-inhibitory
peptide (APP-IP), showed enhanced MMP-7-inhibitory activity. Subsequent
optimization of the peptide moiety led to the development of compound 18 with remarkable potency for MMP-7 and selectivity over
other MMP subtypes