Solid-Phase Synthesis of an "Inaccessible" hGH-Derived Peptide Using a Pseudoproline Monomer and SIT-Protection for Cysteine

The solid-phase peptide synthesis (SPPS) of the C-terminal sequence of hGH with one extra Tyr attached to its N-terminus (total of 16 residues with a disulfide bridge) has been accomplished for the first time by optimizing several synthetic parameters. First of all, the two Ser residues (positions 9 and 13 of the molecule) have been introduced as a single amino acid, Fmoc-Ser(ψMe,Mepro)-OH, demonstrating that the acylation of these hindered moieties is possible. This allows us to avoid the use of the corresponding dipeptides, Fmoc-AA-Ser(ψMe,Mepro)-OH, which are very often not commercially available or very costly. The second part of the sequence has been elongated via a double coupling approach using two of the most effective coupling methods (DIC-OxymaPure and HATU-DIEA). Finally, the disulfide bridging has been carried out very smoothly by a chemoselective thiol-disulfide interchange reaction between a SIT (sec-isoamyl mercaptan)-protected Cys residue and the free thiol of the second Cys. The synthesis of this short peptide has evidenced that SPPS is a multifactorial process which should be optimized in each case.The authors wish to thank Yoav Luxembourg (Luxembourg Biotechnology, Nes Ziona, Israel) for a generous gift of coupling reagents.Peer reviewe

The preventive effect of sensorimotor- and vibration exercises on the onset of Oxaliplatin- or vinca-alkaloid induced peripheral neuropathies - STOP

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and clinically relevant side effect of chemotherapy. Approximately 50% of all leukemia, lymphoma, colorectal-and breast cancer patients are affected. CIPN is induced by neurotoxic chemotherapeutic agents and can manifest with sensory and/or motor deficits. It is associated with significant disability and poor recovery. Common symptoms include pain, altered sensation, reduced or absent reflexes, muscle weakness, reduced balance control and insecure gait. These symptoms not only affect activities of daily living, subsequently reducing patients' quality of life, they have far more become a decisive limiting factor for medical therapy, causing treatment delays, dose reductions, or even discontinuation of therapy, which can affect the outcome and compromise survival. To date, CIPN cannot be prevented and its occurrence presents a diagnostic dilemma since approved and effective treatment options are lacking. Promising results have recently been achieved with exercise. We have revealed that sensorimotor training (SMT) or whole body vibration (WBV) can reduce the symptoms of CIPN and attenuate motor and sensory deficits. We furthermore detected a tendency that it may also have a preventive effect on the onset of CIPN. Methods: We are therefore conducting a prospective, multicentre, controlled clinical trial involving 236 oncological patients receiving either oxaliplatin (N = 118) or vinca-alkaloid (N = 118) who are randomized to one of two interventions (SMT or WBV) or a treatment as usual (TAU) group. Primary endpoint is the time to incidence of neurologically confirmed CIPN. Secondary endpoints are pain, maintenance of the functionality of sensory as well as motor nerve fibres as well as the level of physical activity. The baseline assessment is performed prior to the first cycle of chemotherapy. Subsequent follow-up assessments are conducted at 12 weeks, after completion of chemotherapy, and at a 3-month follow-up. Patients who develop CIPN receive an additional assessment at this time point, as it represents the primary endpoint. Discussion: We hypothesize that SMT and WBV prevent the onset or delay the progression of CIPN, decrease the likelihood of dose reductions or discontinuation of cancer treatment and improve patients' quality of life