Joseph G. McGivern

Targeting N-type and T-type calcium channels for the treatment of pain.

Severe chronic pain afflicts a large number of people worldwide but satisfactory relief from such pain is difficult to achieve with drugs that are currently available, and so there is a great need for the development of new, efficacious and safe analgesics. Voltage-gated calcium-permeable ion channels are multi-subunit complexes that regulate neuronal excitability, action-potential firing patterns and neurotransmission in nociceptive pathways. Although multiple subtypes of voltage-gated calcium channels exist, pharmacological and ion-channel gene knockdown approaches in animals have revealed N-type and T-type calcium channels to be particularly attractive molecular targets for the discovery and development of new analgesic drugs. The recent approval of Prialt (Elan Pharmaceuticals) provides the ultimate target validation for N-type calcium channels, namely proof that they are key regulators of nociceptive signaling in humans.

Voltage-Gated Calcium Channels as Targets for the Treatment of Chronic Pain

This review focuses on the importance of voltage-gated calcium channels in modulating and controlling the function of peripheral and central neurons involved in nociceptive processing. We describe the different families of voltage-gated calcium channels that are expressed in pain pathway neurons, how the expression levels of calcium channel currents change in chronic pain conditions, and the validation of N-type, T-type, and P-type calcium channels as targets for the treatment of pain. The molecular mechanism of action is reviewed for the most prominent calcium channel-targeted drugs including gabapentin and ziconotide as well as antiepileptics administered off-label for the treatment of pain. We discuss how the major genetic, functional, and pharmacological differences between subtypes of neuronal calcium channels can be leveraged to identify new molecular targets and to discover and develop new therapeutic agents for the treatment of chronic pain syndromes.

Advantages of voltage-gated ion channels as drug targets

Many human diseases result from over- or underactivity in one or more critical physiologic systems. One of the foremost challenges in modern drug discovery is the identification and selection of cellular proteins that can be specifically targeted with therapeutic agents in order to normalize aberrant processes/systems. Suitable drug targets must be validated in the human disease state and ideally, the targeted protein will fulfill similar physiologic and pathologic functions in humans and at least one animal species so that in vivo efficacy and toxicology assays with some predictive clinical relevance may be developed. Nowadays, drug targets must also be amenable to high-throughput screening so that novel molecules, which are capable of modifying cellular protein function, can be identified in large libraries of compounds. Voltage-gated ion channels satisfy many of these requirements and, as a class, are viewed as promising drug targets. Nevertheless, despite their relevance to human disease, voltage-gated ion channels remain considerably underexploited. Therein lie some of the opportunities and advantages associated with voltage-gated ion channels as drug targets.

JBS special issue on therapeutic antibody discovery and development: biologics come of age.

In this special issue of the Journal of biomolecular screening, we have assembled a series of articles that exemplify and discuss various aspects and challenges associated with the discovery, development, and manufacture of biologics with an emphasis on those topics that we feel will appeal to readers of this journal. We hope you enjoy them!