Baldomero Olivera

Our major research interest is in molecular mechanisms that underlie nervous system function. Recent conceptual advances in defining key molecules important for signaling nervous systems makes it possible to address how multiple molecular components act sequentially or in concert to yield physiological function. To investigate this, we are developing a set of peptide ligands which target specific receptors and ion channel complexes of neurons; these peptides are found in the venoms of the predatory cone snails, Conus. The neurotoxins made by the venomous Conus (“conotoxins”) are small constrained peptides, each having high affinity for a particular receptor target. The major targets are ion channel families; thus, omega and mu conotoxins target Ca channel and Na receptor families, respectively.

The omega conotoxins have proven to be important research reagents for investigating molecular events that take place at synaptic junctions, since they block neurotransmitter release. Their voltage-gated Ca channel targets are the molecular components which transduce electrical signals of axons into the biochemical events at the presynaptic terminus. Different omega conotoxins are specific for different subtypes of voltage-gated Ca channels; one omega conotoxin originally discovered by our laboratory has been approved as a commercial drug for severe pain. Other families of Conus peptides affect the function of voltage-gated K+ channels.

Other classes of peptides from Conus venoms include the conantokins, the first peptide antagonists which target NMDA receptors, a major class of excitatory receptors in the vertebrate central nervous system, and the α-conotoxins, which target nicotinic acetylcholine receptors. Most Conus peptides are apparently specific for a particular subtype. The venom from a single Conus species contains more than 100 biologically active peptides; the ~700 species of Conus have >50,000 different peptides. The long-range goal is to use these toxins as an entrée for studying key molecules in the CNS. The fact that these toxins can be easily synthesized and labeled with reporter groups will permit a functional characterization of the key CNS targets of these peptides.

The precise mechanism that accounts for the biological activity of most biologically active peptides present in Conus venoms has not yet been determined. A major challenge in the next few years is to elucidate the molecular mechanisms through which the different peptides in Conus venom elicit their often striking behavioral effects.

The enclosed list of publications (last 5 years) are selected for being particularly relevant to the HCI mission. Olivera’s lab works on finding non-opioid molecular targets for severe pain, particularly intractable pain that is no longer relieved by morphine or other opioids. The 16 publications are relevant to this work (total number of publications of the lab in the last 5 years, 55). A particularly important direction is work done by our collaborative group on a peptide that appears to prevent neuropathic pain resulting from chemotherapy; potentially, this could not only alleviate neuropathy as a side effect, but could allow a change in the dose and duration of the chemotherapy to make it significantly more effective. The manuscripts that are directly relevant to these developments are marked with an asterisk.