Synthesis, stability and mechanistic studies of potent anticryptococcal hexapeptides

• Published in: European journal of medicinal chemistry 2017-05, Vol.132, p.192-203
• Main Authors: Shenmar, Kitika, Sharma, Krishna K., Wangoo, Nishima, Maurya, Indresh K., Kumar, Vinod, Khan, Shabana I., Jacob, Melissa R., Tikoo, Kulbhushan, Jain, Rahul
• Format: Article
• Language: English
• Subjects: Amphiphilic hexapeptides; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - pharmacology; Anticryptococcal; Antifungal Agents - chemical synthesis; Antifungal Agents - pharmacology; Cell Membrane - drug effects; Cryptococcus neoformans - drug effects; Drug Stability; Electron microscopy; Inhibitory Concentration 50; Methicillin-Resistant Staphylococcus aureus - drug effects; Peptides - chemical synthesis; Peptides - pharmacology; Proteolysis; Solid phase peptide synthesis; Staphylococcus aureus - drug effects
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.03.046

The growing incidents of cryptococcosis in immuno-compromised patients have created a need for novel drug therapies capable of eradicating the disease. The peptide-based drug therapy offers many advantages over the traditional therapeutic agents, which has been exploited in the present study by synthesizing a series of hexapeptides that exhibits promising activity against a panel of Gram-negative and Gram-positive bacteria and various pathogenic fungal strains; the most exemplary activity was observed against Cryptococcus neoformans. The peptides 3, 24, 32 and 36 displayed potent anticryptococcal activity (IC50 = 0.4–0.46 μg/mL, MIC = 0.63–1.25 μg/mL, MFC = 0.63–1.25 μg/mL), and stability under proteolytic conditions. Besides this, several other peptides displayed promising inhibition of pathogenic bacteria. The prominent ones include peptides 18–20, and 26 that exhibited IC50 values ranged between 2.1 and 3.6 μg/mL, MICs of 5–20 μg/mL and MBCs of 10–20 μg/mL against Staphylococcus aureus and methicillin-resistant S. aureus. The detailed mechanistic study on selected peptides demonstrated absolute selectivity towards the bacterial membranes and fungal cells by causing perturbations in the cell membranes, confirmed by the scanning electron microscopy and transmission electron microscopy studies. A series of hexapeptides containing non-proteiogenic amino acids that exhibit potent inhibition of C. neoformans is reported. [Display omitted] •Synthesis of amphiphilic hexapeptides.•Potent anti-Cryptococcus neoformans activity.•SEM, TEM Microscopic study confirms the activity.•Trypsin assay to confirm the stability of most active peptide.