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Methods of Protein Iodination
Published in Erwin Regoeczi, Iodine-Labeled Plasma Proteins, 2019
The mechanism of amidine formation was studied by Hand and Jencks.134 They conclude that the reaction mechanism is a nucleophilic substitution similar to that occurring in ester aminolysis. The rate-limiting step could be either the addition of the free base of the amine to the cationic form of the imidoester, or the formation of the product.
Brain-Penetrating Reactivators of Organophosphate-InhibitedAcetylcholinesterase
Published in Brian J. Lukey, James A. Romano, Salem Harry, Chemical Warfare Agents, 2019
Janice. E. Chambers, Edward. C. Meek
A series of uncharged amidine oximes were synthesized and tested in vitro and for survival efficacy (Kalisiak et al., 2011, 2012). These showed potential as in vitro reactivators of AChE and butyrylcholinesterase. The survival experiments used a 30 min oxime pretreatment of mice against a soman surrogate and a 5 min post-treatment with oxime against a sarin surrogate, and both paradigms showed excellent survival efficacy of the amidine oximes (Kalisiak et al., 2011, 2012). However, these experimental paradigms were not designed to demonstrate that the enhanced survival was attributable to AChE reactivation in the brain. A subsequent report on these compounds concluded that the successful survival resulted from the enhanced nucleophilicity of the oxime provided by the amidine group and the ability to cross the BBB because of the zwitterionic nature of the compounds (Okolotowicz et al., 2014).
Molecular Recognition and Chemical Modification of Biopolymers — Two Main Components of Affinity Modification
Published in Dmitri G. Knorre, Valentin V. Vlassov, Affinity Modification of Biopolymers, 1989
Dmitri G. Knorre, Valentin V. Vlassov
Another example of one-carbon-bridge cross-linkers are monofunctional alkyl imidates.68 These reagents exclusively modify primary amino groups and are used for protein-protein cross-linking. Modifying amino groups, they give rise to both N-alkyl amidines and imidates which react further with amino groups forming cross-links.
Targeting citrullination in autoimmunity: insights learned from preclinical mouse models
Published in Expert Opinion on Therapeutic Targets, 2021
Ylke Bruggeman, Fernanda M.C. Sodré, Mijke Buitinga, Chantal Mathieu, Lut Overbergh, Maria J.L. Kracht
To date, a variety of reversible and irreversible pan-PAD inhibitors and isozyme-specific PAD inhibitors have been described (Table 1). One of the first potent inhibitors developed is Cl-amidine [31]. Cl-amidine is an irreversible pan-PAD inhibitor that derives its effectivity from a reactive chloroacetamide warhead that covalently modifies the catalytic cysteine in the active site [31], and displays > 5-fold more potency for PAD1 and PAD4 than for PAD3 and PAD2 [32]. The efficacy of Cl-amidine as potential therapeutic has been proven in a variety of preclinical models, as discussed in detail later. However, a major drawback of Cl-amidine is its limited cellular bioavailability that results from a poor metabolic stability and membrane permeability [33]. This drawback was overcome by the design of BB-Cl-amidine that maintains the chloroacetamide warhead, but also holds a benzimidazole and biphenyl moiety limiting proteolysis and improving hydrophobicity, respectively [33]. Compared to Cl-amidine, BB-Cl-amidine is characterized by a superior cellular potency and an increased in vivo half-life (105 versus 15 minutes, approximately) [33]. It is often mistaken that BB-Cl-amidine is a potent PAD2 inhibitor. Although BB-Cl-amidine is slightly more potent to PAD2 compared to Cl-amidine, BB-Cl-amidine has higher potency for PAD1 and PAD4 than PAD3 and PAD2 [34]. BB-Cl-amidine has also proven to be highly effective in preventing autoimmunity in animals models [35,36].
Synthesis and carbonic anhydrase activating properties of a series of 2-amino-imidazolines structurally related to clonidine1
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Niccolò Chiaramonte, Soumia Maach, Caterina Biliotti, Andrea Angeli, Gianluca Bartolucci, Laura Braconi, Silvia Dei, Elisabetta Teodori, Claudiu T. Supuran, Maria Novella Romanelli
Aromatic substitution on the benzyl moiety did not improve the potency: in fact, while the 4-Cl derivative 13 was equiactive with 11, a 4-OMe (14) or 4-F substituent (15) increased from 2 to 3.5 times the KA values. The same substituents in the meta position reduced to a higher extent or abolished the activity. As far as the sulphur analogues 1a, 23 and 24 are concerned, the small methyl group seemed tolerated, not the bulkier benzyl moiety (24, KA >150 µM). The basicity of the amidine group appeared to be not crucial, since the NH and the N-acetyl derivatives (1a and 23, respectively) were equipotent.
Peptidyl arginine deiminase inhibition suppresses arthritis via decreased protein citrullination in joints and serum with the downregulation of interleukin-6
Published in Modern Rheumatology, 2019
Hoshimi Kawaguchi, Isao Matsumoto, Atsumu Osada, Izumi Kurata, Hiroshi Ebe, Yuki Tanaka, Asuka Inoue, Naoto Umeda, Yuya Kondo, Hiroto Tsuboi, Akihito Ishigami, Takayuki Sumida
Next, we examined whether Cl-amidine treatment affected autoantibody production. Anti-pGPI antibodies titers were not significantly different by Cl-amidine treatment (Figure 1(C)). ACPA titers from Cl-amidine-treated mice tended to be lower than controls, but not significantly different (Figure 1(D)). On the other hand, ACPA titers were significantly higher on Day 14 compared to Day 0 in control mice, while there was no significant elevation in ACPA titers on Day 14 in Cl-amidine-treated mice. These results suggest that the inhibition of PAD by Cl-amidine suppresses the severity of arthritis in pGIA, and involvement of ACPA may be partial.