Design, Synthesis and Characterization of [G10a]-Temporin SHa Dendrimers as Dual Inhibitors of Cancer and Pathogenic Microbes.

As the technologies for peptide synthesis and development continue to mature, antimicrobial peptides (AMPs) are being widely studied as significant contributors in medicinal chemistry research. Furthermore, the advancement in the synthesis of dendrimers' design makes dendrimers wonderful nanostructures with distinguishing properties. This study foregrounds a temporin SHa analog, [G10a]-SHa, and its dendrimers as globular macromolecules possessing anticancer and antibacterial activities. These architectures of temporin SHa, named as [G10a]-SHa, its dendrimeric analogs [G10a]2-SHa and [G10a]3-SHa, and [G10a]2-SHa conjugated with a polymer molecule, i.e., Jeff-[G10a]2-SHa, were synthesized, purified on RP-HPLC and UPLC and fully characterized by mass, NMR spectroscopic techniques, circular dichroism, ultraviolet, infrared, dynamic light scattering, and atomic force microscopic studies. In pH- and temperature-dependent studies, all of the peptide dendrimers were found to be stable in the temperature range up to 40-60 °C and pH values in the range of 6-12. Biological-activity studies showed these peptide dendrimers possessed improved antibacterial activity against different strains of both Gram-positive and Gram-negative strains. Together, these dendrimers also possessed potent selective antiproliferative activity against human cancer cells originating from different organs (breast, lung, prostate, pancreas, and liver). The high hemolytic activity of [G10a]2-SHa and [G10a]3-SHa dendrimers, however, limits their use for topical treatment, such as in the case of skin infection. On the contrary, the antibacterial and anticancer activities of Jeff-[G10a]2-SHa, associated with its low hemolytic action, make it potentially suitable for systemic treatment.

Discovery of stylissatin A analogs exhibiting potent nitric oxide inhibition.

The cyclic peptide stylissatin A(STA) was obtained from the Papua New Guinean marine spongeStylissamassaas a potent nitric oxide (NO) inhibitor.Among its reported analogs,cyclo-{Glu6, Ala2}-STA1potentlyinhibited theinterleukin-2 and proliferation of T-cells indicating position 2 of sequence playing important part in biological activities of this compound.In current studies, second generation analogs of STAwere synthesizedaround its most active analog1by screening position 2 of analog1with different amino acid. All analogs2-6were identified by mass, and NMR techniques.The synthesized analogswere also evaluated against NO generation by lipopolysaccharide (LPS)-stimulated murine J774.2macrophages, ROS inhibition from whole blood phagocytes, and T-cell proliferation from Jurkat cells.All analogswere found to be inactive towards interleukin-2, T-cells proliferation, and ROS inhibition. The analog2showed a potent suppression of NO (IC50 = 46.0 ± 2.2 µM) that was superior to the activityreported for natural product STA.Further attempts to optimizeanalog2afforded new nitric oxide inhibitors2a-2fwhich were found less active than2.The analog2also downregulated the transcription of pro-inflammatory molecules, tumor necrosis factor-α, interlukin-1ß, caspase-1 and ASC which further highlights its anti-inflammatory and possible therapeutic potential. Analog2was non-toxic to BJ and Vero cell lines of normal mammalian origin.