Exploiting a novel conformational switch to control innate immunity mediated by complement protein C3a

Abstract

Complement C3a is an important protein in innate and adaptive immunity, but its specific roles in vivo remain uncertain because C3a degrades rapidly to form the C3a-desArg protein, which does not bind to the C3a receptor and is indistinguishable from C3a using antibodies. Here we develop the most potent, stable and highly selective small molecule modulators of C3a receptor, using a heterocyclic hinge to switch between agonist and antagonist ligand conformations. This enables characterization of C3 areceptor-selective pro- vs. anti-inflammatory actions in human mast cells and macrophages, and in rats. A C3a receptor-selective agonist induces acute rat paw inflammation by first degranulating mast cells before activating macrophages and neutrophils. An orally administered C3a receptor-selective antagonist inhibits mast cell degranulation, thereby blocking recruitment and activation of macrophages and neutrophils, expression of inflammatory mediators and inflammation in a rat paw edema model. These novel tools reveal the mechanism of C3a-induced inflammation and provide new insights to complement-based medicines.

Modulation of Conformational Preferences of Heteroaromatic Ethers and Amides through Protonation and Ionization: Charge Effect

“…For other heteroaromatic compounds like amides, some of which have recently been explored as drugs, the effect of protonation and oxidation on their conformational preferences are similar to that of heteroaromatic ethers. For the amides containing one or two heteroatoms (Figure ), all the protonated ones are anti ‐preferring, while all the ionized ones are syn ‐preferring, as shown in Table .…”

“…Understanding key factors determining conformation will help to select heteroaromatic templates for elaboration in drug discovery and performance. For the recently developed C3a agonist/antagonist (compounds 54 and 55 ) from different conformers or several kinds of inhibitors (EGFR 56 , Hsp70 58 , factor Xa 59 and MAP kinase inhibitor 60 ) containing structures similar to o ‐heteroaromatic ethers or amides, the pH or redox effect should be taken into account in their design or function (Figure ). Additionally, the conformational fixation of amide has been used as a new synthetic method, in the ring‐closing metathesis to yield medium‐sized lactams …”

“…Conformational preference and switching are of theoretical and practical importance. The origin of conformational preference and internally rotational barrier has long been related to the steric, quantum and electrostatic effects .…”

“…Heterocycles are usually important components of natural compounds and functional molecules and can influence molecular conformation and properties. Since the heterocyclic ring adjacent to an ether oxygen or amide can determine molecular conformation, they can be used as heterocyclic hinges to orient a chain in conformational space . In drug design, this kind of heterocyclic hinge has been used as switch between agonist and antagonist ligand conformations .…”

“…Since the heterocyclic ring adjacent to an ether oxygen or amide can determine molecular conformation, they can be used as heterocyclic hinges to orient a chain in conformational space . In drug design, this kind of heterocyclic hinge has been used as switch between agonist and antagonist ligand conformations . Strong conformational preferences of 2‐methoxyheteroarenes induced by electron pair repulsion make the heteroaromatic ether bond a potential conformational switch .…”