Frontiers in Medicinal Chemistry

There is a brief summary of the early background literature about purinergic signalling and its involvement in pain, of ATP storage, release and ectoenzymatic breakdown and of the current classification of receptor subtypes for purines and pyrimidines. The review then focuses on purinergic mechanosensory transduction involved in visceral, cutaneous and musculoskeletal nociception and on the roles played by P2X3, P2Y2/3, P2X4, P2X7 and P2Y12 receptors in neuropathic and inflammatory pain. Current developments of compounds for the therapeutic treatment of both visceral and neuropathic pain are discussed.

Apoptosis is a highly programmed cell death process that can be activated by various factors and is strictly connected to the pathogenesis of many human diseases, including neoplastic, neurodegenerative or cardiovascular diseases. Mitochondria play a key role in the apoptotic process. The permeabilization of the outer mitochondrial membrane, occurring as mitochondrion is damaged, activates a series of events leading to cell death. Apoptosis is activated by various factors; among the various hypotheses formulated, the so-called ‘intrinsic’ pathway theory assumes that the process, which initiates in the mitochondrion, provokes the release of cytochrome c and other proapoptotic factors from the mitochondrial intermembrane space to cytosol. In the cytosol, cytochrome c exerts a pro-apoptotic action binding to the apoptosis protease activation factor (APAf-1) and forming a complex called ‘apoptosome’. The activation of procaspase 9 initiates an enzymatic reaction cascade leading to cell death. This review provides an overview of the key role played by mitochondria and cytochrome c in activating the apoptotic process.

Dipeptidyl peptidase-4 (DPP4) or adenosine deaminase complexing protein 2 (ADCP 2) or T-cell activation antigen CD26 (EC 3.4.14.5.) is a serine exopeptidase belonging to the S9B protein family that cleaves X-proline dipeptides from the N-terminus of polypeptides, such as chemokines, neuropeptides, and peptide hormones. The enzyme is a type II transmembrane glycoprotein, expressed on the surface of many cell types, whose physiological functions have begun to emerge in recent years. Protein dimerisation is required for catalytic activity and glycosylation of the enzyme could impact on its physiological functions. The dimeric glycoprotein ADCP has been found linked to adenosine deaminase (ADA) whose relationship with lymphocyte maturationdifferentiation is well established.

Since implicated in the regulation of the biological activity of hormones and chemokines, such as glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, DPP4 inhibition offered a new potential therapeutic approach for type 2 diabetes mellitus as monotherapy and adjunct therapy to other oral agents. The clinical use of orally active inhibitors of DPP4 has been initially associated with side effects that have been in part attributed to the inhibition of related serine proteases, such as DPP8 and DPP9. Moreover, CD26 has a key role in immune regulation as a T cell activation molecule and in immune-mediated disorder; all-cause infections were found increased after sitagliptin treatment. So far, systematic reviews and meta-analysis on the efficacy and safety in human type 2 diabetes of orally active DPP4 inhibitors were published, but some questions remain open. Long-term evaluation of the risk-benefit ratio in controlled trials is still required, possibly through the use of multiple risk-benefit approaches across different indications and treatment populations. The review summarises present knowledge in the field and suggests some potential directions of future research.

Angiogenesis regulation strictly depends on the balance between pro- and anti-angiogenic molecules such as growth factors. Growth factors exert their biological action selectively binding to and activating specific cell membrane receptors which then transfer the message to cell interior triggering specific biochemical pathways ending in the angiogenic response. Molecules able to interfere with the molecular recognition between an angiogenic growth factor and its receptor can modulate the angiogenesis. Peptides are good candidates to develop new lead compounds able to target the growth factor-receptor protein interface for pharmacological applications. In this review we describe peptides targeting the receptors of the pro-angiogenic growth factors Fibroblast Growth Factor, Platelet-Derived Growth Factor and Vascular Endothelial Growth Factor. The biological function and the three-dimensional structure of each growth factor/receptor system are discussed, as well as the molecular interaction between peptides and the receptors. Finally, we highlight the pharmacological and diagnostic applications of these peptides in angiogenesis related diseases.

Considerable scientific evidence has been obtained that suggests that the melanocortin 3 and melanocortin 4 receptors are critically involved in energy balance and feeding behavior in animals, including humans. The natural ligands for these receptors are processed products of the gene pro-opiomelanocortin (POMC) and include α-, β- and γ- melanocyte stimulating hormones and possibly other POMC products. Hence, it has been postulated that selective agonists and antagonists might serve as drugs for the treatment of feeding disorders. At the same time, it was found that melanotropin peptides can have other biological activities related to the MC3R and MC4R, and that some of these activities, such as blood pressure changes, need to be modulated in order to be useful drugs without unwarranted side effects. Current progress in these efforts will be discussed along with possible new directions that might be useful in these important areas of biology and medicine.

Packaging small-molecule drugs into nanoparticles improves their bioavailability, bio-compatibility and safety profiles. Multifunctional particles carrying large drug payloads for targeted transport, immune evasion and favourable drug release kinetics at the target site, require a certain minimum size usually 30-300 nm diameter, so are nanoparticles. Targeting particles to a disease site can signal the presence of the disease site, block a function there, or deliver a drug to it. Targeted nanocarriers must navigate through blood-tissue barriers, varying in strength between organs and highest in the brain, to reach target cells. They must enter target cells to contact cytoplasmic targets; specific endocytotic and transcytotic transport mechanisms can be used as trojan horses to ferry nanoparticles across cellular barriers. Specific ligands to cell surface receptors, antibodies and antibody fragments, and aptamers can all access such transport mechanisms to ferry nanoparticles to their targets. The pharmacokinetics and pharmacodynamics of the targeted drug-bearing particle depend critically on particle size, chemistry, surface charge and other parameters. Particle types for targeting include liposomes, polymer and protein nanoparticles, dendrimers, carbon-based nanoparticles e.g. fullerenes, and others. Immunotargeting by use of monoclonal antibodies, chimaeric antibodies and humanized antibodies has now reached the stage of clinical application. High-quality targeting groups are emerging: antibody engineering enables generation of human/like antibody (fragments) and facilitates the search for clinically relevant biomarkers; conjugation of nanocarriers to specific ligands and to aptamers enables specific targeting with improved clinical efficacy. Future developments depend on identification of clinically relevant targets and on raising targeting efficiency of the multifunctional nanocarriers. The complexity and expense of translational work with nanoparticles has prompted regulatory agencies and funding organizations to adapt regulatory frameworks and establish programs to facilitate preclinical testing.