Research Projects

Neuropathic pain is a significant comorbidity of patients with cancer, diabetes, HIV infection, multiple myeloma, multiple sclerosis, stroke, and arthritis in the spine. It also manifests in patients receiving chemotherapy or having undergone spine surgery. Neuropathic pain is commonly chronic and usually manifests as shooting or burning pain. It is typically a malfunctioning nervous system. However, proper mechanisms and appropriate therapies are still elusive. Prevalent treatments only provide an easing effect. Some α-conotoxins (from cone snail) offered great hope to be used against neuropathic pain, being antagonists of nicotinic acetylcholine receptors (nAChRs). Inhibition of α9 α10 nAChRs have been demonstrated as an effective non-opioid strategy in attenuating neuropathology after trauma-induced nerve damage. Structurally, α-conotoxins comprise 12–19 amino acids with well-defined folds having helical regions having two disulfide bonds for stabilization. Conserved proline residue in the loop remains an essential structural feature of the α-conotoxins. The major caveat for the human use of conotoxins is their vulnerability to degradation by endogenous proteases. The proteolytic stability of these peptide toxins can be improved by incorporating the disulfide bonds with diselenide bonds, additional N-& C-terminal capping, altering the stereochemical configuration at specific positions, truncation, conjugation with the lipophilic group at N-terminus and joining of N- & C-ends. Incorporating the non-protein amino acid at specific positions could also be a practical step to increase the antagonistic activity of alpha-conotoxins. It is proposed here to develop the synthetic mimics of α-conotoxins (i.e., α4/7, α4/4, and α4/3 subfamilies) that are impervious to proteolytic degradation to block the neuronal nAChR to attenuate chronic pain in cellular and animal models. The project will entail the design and synthesis of peptide libraries incorporating non-protein amino acids and selenocysteine derived from native conotoxins, their purification, and structural characterization using biophysical techniques. Neuropharmacological evaluation of the designed peptide libraries will be pursued using cellular models of neuropathic pain using rodent spinal cord neurons by quantification of relevant markers for chronic pain. Further, the most potent conotoxin analogs will be assessed for pain-mitigating effects (biochemical and behavioral) after sciatic nerve ligation-induced neuropathic pain in rodents.