Comparison of Peganum harmala L. leaves extract nanoformulations against herpes simplex virus type 1 guided by network pharmacology analysis.

Herpes simplex virus type 1 (HSV-1) is a highly prevalent viral infection with limited medications. Thus, search for safe and effective alternative treatments is urgently needed. Peganum harmala L. (P. harmala) praised with antiviral potential may afford a decent option against HSV-1. This study creatively integrated network pharmacology and nanoscience to objectively disclose the efficacy mechanism of P. harmala bioactive compounds and augment the antiviral potential of P. harmala against HSV-1 via nanotechnology. Network pharmacology analysis revealed MAPK 1, SRC, EGFR and JAK1 as the top putative HSV-1 genes highly enriched in MAPK, PI3K-Akt, and JAK-STAT signalling pathways and primarily associated with the efficacy mechanism of P. harmala bioactive compounds against HSV-1. Complementarily, four P. harmala nano-formulations were established, monitored using different pharmaceutical scores, and assessed against HSV-1 using plaque reduction assay. Experimentally speaking, P. harmala-CS-ZnO NPs showed higher zeta (+ 40.8) with particle-size (73.06 nm), higher entrapment (81.7%) with loading-capacity (6.8%), sustained release reaching 50.5% after 24 h and demonstrated the most promising observation against HSV-1, with viral inhibition of 54.1% which is double the effect of crude extract alone with acceptable cytotoxicity (CC50 = 271.4 µg/ml). This enhanced effect is possibly due to the synergistic antiviral properties of P. harmala bioactive compounds, chitosan, and zinc oxide nanoparticles. This complex between the ingredients chemically detected by FT-IR analysis also improved stability, cellular uptake, viral inhibition, and bioavailability. Our findings offer a solid basis for more extensive and rational clinical integration of P. harmala in the pharmaceutical industry to rectify human herpes viruses.