| Autor: |
Sharma K; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar 160 062, Punjab, India., Aaghaz S; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar 160 062, Punjab, India., Maurya IK; Center of Infectious Diseases, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar 160 062, Punjab, India., Singh S; Department of Medical Microbiology, Post Graduate Institute of Medical Education and Research, Sector 12, Chandigarh 160 012, India., Rudramurthy SM; Department of Medical Microbiology, Post Graduate Institute of Medical Education and Research, Sector 12, Chandigarh 160 012, India., Kumar V; Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar 160 062, Punjab, India., Tikoo K; Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar 160 062, Punjab, India., Jain R; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar 160 062, Punjab, India. |
| Abstrakt: |
Delineation of clinical complications secondary to fungal infections, such as cryptococcal meningitis, and the concurrent emergence of multidrug resistance in large population subsets necessitates the need for the development of new classes of antifungals. Herein, we report a series of ring-modified histidine-containing short cationic peptides exhibiting anticryptococcal activity via membrane lysis. The N -1 position of histidine was benzylated, followed by iodination at the C-5 position via electrophilic iodination, and the dipeptides were obtained after coupling with tryptophan. In vitro analysis revealed that peptides Trp-His[1-(3,5-di- tert -butylbenzyl)-5-iodo]-OMe ( 10d , IC 50 = 2.20 μg/mL; MIC = 4.01 μg/mL) and Trp-His[1-(2-iodophenyl)-5-iodo)]-OMe ( 10o , IC 50 = 2.52 μg/mL; MIC = 4.59 μg/mL) exhibit promising antifungal activities against C. neoformans . When administered in combination with standard drug amphotericin B (Amp B), a significant synergism was observed, with 4- to 16-fold increase in the potencies of both peptides and Amp B. Electron microscopy analysis with SEM and TEM showed that the dipeptides primarily act via membrane disruption, leading to pore formation and causing cell lysis. After entering the cells, the peptides interact with the intracellular components as demonstrated by confocal laser scanning microscopy (CLSM). |
