Targeting the minor pocket of C5aR for the rational design of an oral allosteric inhibitor for inflammatory and neuropathic pain relief

Abstract

Significance Persistent pain in inflammatory and neuropathic conditions is often refractory to conventional analgesic therapy, with most patients suffering with unrelieved pain and serious treatment-related side effects. There is still a tremendous need to identify novel therapeutics for pain control with innovative biological mechanisms and minimal side effects. In this paper we challenge the hypothesis that a conserved structural motif across the G protein-coupled receptor family plays a regulatory role in the negative modulation of receptor activation and use a multidisciplinary approach to the rational drug design and characterization of a novel potent allosteric inhibitor of the C5a anaphylatoxin receptor (C5aR), thus providing a new promising avenue for the improvement of pharmacotherapy of chronic pain.

Allosterism in human complement component 5a (hC5a): a damper of C5a receptor (C5aR) signaling

“…Nonetheless, barring des-Arg 74 -h C5a, no such detailed structural studies on the other known pharmacophores of h C5a have been undertaken so far. In fact, the structural studies (Cook et al, 2010) also do not provide sufficient insight to decipher the possible allosteric phenomena in h C5a in solution and its role in C5aR signaling (Moriconi et al, 2014). This provides the necessary momentum and the opportunity to study the structure-function relationship in the pharmacophores of h C5a by implementing the other available alternative techniques.…”

“…Human C5a ( h C5a) is one such cationic glycoprotein ligand (Klos, Wende, Wareham, & Monk, 2013), which is known to interact with two GPCRs, such as C5aR and C5L2 (Guo & Ward, 2005). While allosterism in C5aR has been discussed in the literature (Moriconi et al, 2014), it is yet to be discussed in h C5a. The h C5a-C5aR interaction is of therapeutic importance, as it elicits a plethora of physiological responses ranging from chemoattraction, multiple organ failure, ischemia, and reperfusion injury to apoptosis (Guo & Ward, 2005).…”

The renaissance of complement therapeutics

“…The preclinical drug candidate DF2593A (Dompé) reportedly binds to a distinct pocket on C5aR1 and acts as an allosteric modulator of the receptor 174 ; inflammatory and neuropathic pain are listed as potential indications. Innate Pharma is currently focusing preclinical development efforts on an antibody (IPH-5401) to block C5aR1 activity 175 .…”

Molecular and cellular mechanisms that initiate pain and itch

“…Although it remains unclear if neutrophils contribute to the genesis of pruritus, they have complex effects on pain sensation. Pharmacological inhibition or genetic ablation of the function of chemoattractive factors including C5a receptor [42] and keratinocyte-derived chemokine [43] reduces or prevents behavioral hypersensitivity in neuropathic pain models. Inhibition of leukocyte adhesion and migration also reduces mechanical hyperalgesia caused by partial sciatic nerve ligation [44, 45].…”