Editorial: Small molecules and biologics for future purinergic therapeutics

Abstract

Receptor agonists and antagonists and other modulators of purinergic signalling have potential as novel therapeutics for a broad range of diseases and conditions. This special issue focuses on compounds or approaches that are either in clinical trials or headed in that direction. It is intended to serve as an up-to-date description of selected efforts to discover and develop new small molecular purinergic drugs.

The receptors of the purinergic signalling system (adenosine, P2X and P2Y receptors) are implicated in conditions of the nervous system, the immune system and many other systems [1–3]. Adenosine is an endogenous agent for suppressing seizures, ischemic damage and pain [1], while ATP and other nucleotides often act as damage-associated molecular patterns (DAMPs) and are proinflammatory [2, 3]. How can these pathways be modulated selectively for therapeutic benefit? The nineteen established purinergic receptors and the enzymes that regulate the levels of endogenous activators now have numerous definitive tool compounds, as well as in some cases druglike clinical molecules. Recent development of highly selective or biased ligands, including allosteric modulators, provides new opportunities for drug development for the nervous system and other physiological systems.

This special issue of Purinergic Signalling is intended to reflect the growing interest in purinergic therapeutics. The seven contributed papers describe both small molecule modulators (including purely research tools) and the biological pathways suggesting a potential new direction for therapeutics. Three papers relate to the P2X receptor family, one relates to the P2Y₁₁ receptor, and the remainder relate to the adenosine receptor family, principally A₃. There are no papers on ectonucleotidase inhibitors, which is also an important therapeutic direction.

Pelleg et al. have characterized pharmacologically a novel P2X3 receptor antagonist that is being developed commercially for the treatment of chronic cough, by reversing vagal sensory nerve-induced bronchoconstriction [4]. Unlike other nonnucleotide P2X3 receptor antagonists that have already been in the clinic for chronic cough [5], DT-0111 is a 3’-acylamino-3’-deoxy derivative of ATP. Nevertheless, it is highly selective for the homotrimeric P2 × 3 receptor compared to the P2X2/3 heterotrimer. Song et al. propose the use of P2X4 antagonists for treating chronic pain, based on the mechanical hyperalgesia induced by P2 × 4 receptor activation in the cerebrospinal fluid-contacting nucleus in a chronic constriction injury rat model [6]. To place this chapter in context, other groups have shown P2X4 antagonists to be effective in other vivo chronic pain models [2, 7, 8]. Gamiotea-Turro et al. have used NextGen RNA SEQ to analyse the potential gene changes involved in stroke protection by knockout of the P2X4 receptor in mice [9]. They found inflammation and extracellular matrix component genes to be enriched, but curiously without age-dependent differences. They validated by qPCR the reduction observed in certain inflammatory genes in the knockout tissue. In a similar context, stroke protection in mice was observed previously using P2X4 receptor-selective antagonists [2]. Klaver and Thurnher review studies suggesting a crosstalk between the P2Y₁₁ receptor [10], a subtype not frequently implicated in a therapeutic context, and interleukin (IL)-1-mediated anti-inflammatory effects in human M2 macrophages. This anti-inflammatory pathway is G_s-mediated, although the receptor also signals through the more commonly studied G_q protein.

Four papers concern adenosine receptors, which have been the focus of numerous clinical studies for decades. The pharmaceutical research group that is principally involved in clinical trials of multiple modulators of the A₃ adenosine receptor, i.e. Fishman et al., has provided an up-to-date review of the mechanism and efficacy of an A₃ adenosine receptor agonist, namodenoson (also known as Cl-IB-MECA), to treat liver conditions, including hepatocellular carcinoma and nonalcoholic steatohepatitis (NASH) [11]. Tool compounds for purinergic receptors can greatly facilitate pharmacological studies. Toti et al. have disclosed new fluorescent antagonists of the A_2A and A₃ adenosine receptors and demonstrated their feasibility of use as flow cytometry probes, or as screening and or visualization tools that can enable drug development [12]. The A₃ adenosine receptor has distinct species differences in its pharmacology and function, as well as affinity of various ligand classes, especially antagonists and positive allosteric modulators (PAMs), as described in Gao et al. [13]. C57BL/6 mice lacking all four adenosine receptors are surprisingly viable and comparable to wild-type by most phenotypic criteria, except that adenosine does not reduce activity or core body temperature, and caffeine does not stimulate activity. This quadruple KO (QKO) mouse line was applied to validate (or contradict) reports that numerous non-adenosine drugs display the incidental activity through adenosinergic signaling [14], including nimodipine, cilostazol and cyclosporin A. These three approved drugs increase adenosinergic signaling in vivo by blocking nucleoside transport, and their hypothermic effects disappear in QKOs. That approach can lead to drug repurposing of approved drugs and treatments to boost adenosine signalling.

Thus, multiple lines of inquiry are leading to new opportunities for the clinical implementation of purinergic signalling modulators, only a few representative examples of which are included in this special issue.

Declarations

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.