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Recent studies have shown that modified human lactoferrin 20–31 fragment, named HLopt2, possesses antibacterial and antifungal activity. Thus, we decided to synthesize and evaluate the biological activity of a series of conjugates based on this peptide and one of the antimicrobials with proven antibacterial (ciprofloxacin, CIP, and levofloxacin, LVX) or antifungal (fluconazole, FLC) activity. The drugs were covalently connected to the peptide via amide, methylenecarbonyl moieties, or a disulfide bridge. The antibacterial and antifungal activities were evaluated under Clinical and Laboratory Standard Institute (CLSI) recommended conditions or in a low-salt brain–heart infusion diluted medium (BHI1/100). Results showed that conjugation of the peptide with the drug increased its antimicrobial activity up to 4-fold. Under CLSI-recommended conditions, all the compounds revealed rather low efficiency. Among conjugates, the highest antibacterial activity was recorded for the CIP-Cys-S-S-HLopt2-NH2(III). In BHI1/100, which had lower differentiating properties, all of the conjugates revealed low MIC and MMC (minimum inhibitory and microbicidal concentrations) values. The disulfide bridge used as a linker in the most active conjugate (III) upon incubation with S. aureuscells is reduced, releasing constituent peptide and CIP-Cys. In addition, we showed that its fluorescently labeled analogue and constituent peptide are able to be internalized into both C. albicansand S. aureuscells. Moreover, the invaluable advantage of the presented conjugates was their low toxicity to mammalian cells and very low hemolytic activity. The current research can form a solid basis for further in vivostudies and drug development.

Parkinson’s disease (PD) is a common progressive neurodegenerative disorder for which the current treatment is not fully satisfactory. One of the major drawbacks of current PD therapy is poor penetration of drugs across the blood-brain barrier (BBB). In recent years, cell-penetrating peptides (CPPs) such as Tat, SynB, or TP10 have gained great interest due to their ability to penetrate cell membranes and to deliver different cargos to their targets including the central nervous system (CNS). However, there is no data with respect to the use of CPPs as drug carriers to the brain for the treatment of PD. In the presented research, the covalent TP10-dopamine conjugate was synthesized and its pharmacological properties were characterized in terms of its ability to penetrate the BBB and anti-parkinsonian activity. The results showed that dopamine (DA) in the form of a conjugate with TP10 evidently gained access to the brain tissue, exhibited low susceptibility to O-methylation reaction by catechol-O-methyltransferase (lower than that of DA), possessed a relatively high affinity to both dopamine D1and D2receptors (in the case of D1, a much higher than that of DA), and showed anti-parkinsonian activity (higher than that of l-DOPA) in the MPTP-induced preclinical animal model of PD. The presented results prove that the conjugation of TP10 with DA may be a good starting point for the development of a new strategy for the treatment of PD.

Summary: Galanin (GAL), a 29-amino-acid-residue neuropeptide, modulates gastric smooth muscles activity by interacting with specific receptors. However due to the lack of specific antagonists in the gastrointestinal (GI) tract the actual level of GAL involvement in GI motility remains largely unknown. In our studies we have performed structure-activity relationship studies of two porcine galanin fragments, two chimeric galanin analogues and several 15-amino-acid-residue galanin analogues modified in positions 2, 3, 4, 6, 8 or 14, investigating their contractile action on rat isolated gastric fundus strips, employed as in vitro assay of peptides activity. Thus we intended to characterize the molecular domains of GAL responsible for binding and activation of GAL receptors in rat gastric smooth muscle cells. The data acquired in the course of our structure-activity relationship studies suggest that both N-and C-terminal fragment of GAL molecule contribute towards the affinity and activity of GAL gastric smooth muscle cell receptors. Moreover, we concluded that positions 2, 3, 4, 6, 8 and 14 in the amino acid sequence of GAL may play important roles in binding and activation of GAL receptors in rat gastric smooth muscle cells.

Galanin (GAL), a 29-amino-acid-residue neuropeptide, modulatesgastric smooth muscles activity by interacting with specific receptors. However due to the lack of specific antagonists in thegastrointestinal (GI) tract the actual level of GAL involvement in GI motility remains largely unknown. In our studies we have performed structure-activity relationship studies of two porcinegalanin fragments, two chimeric galanin analogues and several 15-amino-acid-residue galanin analogues modified in positions 2, 3, 4, 6, 8 or 14, investigating their contractile action on rat isolated gastric fundus strips, employed as in vitro assay of peptides activity. Thus we intended to characterize the moleculardomains of GAL responsible for binding and activation of GAL receptors in rat gastric smooth muscle cells. The data acquired in the course of our structure-activity relationship studies suggest that both N- and C-terminal fragment of GAL molecule contribute towards the affinity and activity of GAL gastric smooth muscle cell receptors. Moreover, we concluded that positions 2, 3, 4, 6, 8 and 14 in the amino acid sequence of GAL may play important roles in binding and activation of GAL receptors in rat gastric smooth muscle cells.

Galanin (GAL), a 29-amino-acid-residue neuropeptide, modulates gastric smooth muscles activity by interacting with specific receptors. However due to the lack of specific antagonists in the gastrointestinal (GI) tract the actual level of GAL involvement in GI motility remains largely unknown. In our studies we have performed structure-activity relationship studies of two porcine galanin fragments, two chimeric galanin analogues and several 15-amino-acid-residue galanin analogues modified in positions 2, 3, 4, 6, 8 or 14, investigating their contractile action on rat isolated gastric fundus strips, employed as in vitro assay of peptides activity. Thus we intended to characterize the molecular domains of GAL responsible for binding and activation of GAL receptors in rat gastric smooth muscle cells. The data acquired in the course of our structure-activity relationship studies suggest that both N-and C-terminal fragment of GAL molecule contribute towards the affinity and activity of GAL gastric smooth muscle cell receptors. Moreover, we concluded that positions 2, 3, 4, 6, 8 and 14 in the amino acid sequence of GAL may play important roles in binding and activation of GAL receptors in rat gastric smooth muscle cells.