Enhancing Specific Disruption of Intracellular Protein Complexes by Hydrocarbon Stapled Peptides Using Lipid Based Delivery

Linear peptides can mimic and disrupt protein-protein interactions involved in critical cell signaling pathways. Such peptides however are usually protease sensitive and unable to engage with intracellular targets due to lack of membrane permeability. Peptide stapling has been proposed to circumvent these limitations but recent data has suggested that this method does not universally solve the problem of cell entry and can lead to molecules with off target cell lytic properties. To address these issues a library of stapled peptides was synthesized and screened to identify compounds that bound Mdm2 and activated cellular p53. A lead peptide was identified that activated intracellular p53 with negligible nonspecific cytotoxicity, however it still bound serum avidly and only showed a marginal improvement in cellular potency. These hurdles were overcome by successfully identifying a pyridinium-based cationic lipid formulation, which significantly improved the activity of the stapled peptide in a p53 reporter cell line, principally through increased vesicular escape. These studies under score that stapled peptides, which are cell permeable and target specific, can be identified with rigorous experimental design and that these properties can be improved through use with lipid based formulations. This work should facilitate the clinical translation of stapled peptides

Modified transcorporeal anterior cervical microforaminotomy for cervical radiculopathy: a technical note and early results

A prospective analysis of the first twenty patients operated for cervical radiculopathy by a new modification of transcorporeal anterior cervical foraminotomy technique. To evaluate early results of a functional disc surgery in which decompression for the cervical radiculopathy is done by drilling a hole in the upper vertebral body and most of the disc tissue is preserved. Earlier approaches to cervical disc surgery either advocated simple discectomy or discectomy with fusion, ultimately leading to loss of motion segment. Posterior foraminotomy does not address the more common anterior lesion. Twenty patients suffering from cervical radiculopathy not responding to conservative treatment were chosen for the new technique. Upper vertebral transcorporeal foraminotomy was performed with the modified technique in all the patients. All the patients experienced immediate/early relief of symptoms. No complications of vertebral artery injury, Horner’s syndrome or recurrent laryngeal nerve palsy were noted. Modified transcorporeal anterior cervical microforaminotomy is an effective treatment for cervical radiculopathy. It avoids unnecessary violation of the disc space and much of the bony stabilizers of the cervical spine. Short-term results of this technique are quite encouraging. Longer-term analysis can help in outlining the true benefits of this technique