Mechanistic study of inhibitory peptides with SHP-1 in hypertonic environment for infection model

• Published in: Biochimica et biophysica acta. General subjects Vol. 1868; no. 9; p. 130670
• Main Authors: Khandibharad, Shweta, Singh, Shailza
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.09.2024
• Subjects: Animals; cutaneous leishmaniasis; Disease Models, Animal; Humans; Infection and high salt diet; infectious diseases; inflammation; interleukin-10; Interleukin-10 - metabolism; interleukin-12; Interleukin-12 - metabolism; Leishmania major; Leishmaniasis, Cutaneous - drug therapy; Leishmaniasis, Cutaneous - metabolism; Leishmaniasis, Cutaneous - parasitology; Leishmaniasis, Cutaneous - pathology; mammals; Membrane; Mice; Mice, Inbred BALB C; molecular dynamics; Molecular Dynamics Simulation; parasite load; parasites; Peptide; Peptides - chemistry; Peptides - metabolism; Peptides - pharmacology; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - metabolism; skin lesions; sodium; therapeutics; World Health Organization; PepB; PepA; M1; M2; DBD; GLN; MCMC; RoG; H2O2; PepC; BSA; L.major; PepC-SHP1; FBS; HSD; iNOS; DMPC; Peptide; MDS; PSA; AED; PBS; BCA; Infection and high salt diet; H&E; DAPI; Molecular dynamics simulation; PLDS; NaCl; SASA; ELISA; NFAT5; NO; PepA-SHP1; GP63; FACS; SHP-1; RIPA; NPT; Membrane; ASN; intraHB; Interleukin-10; NOS2; Interleukin-12; PepB-SHP1; RMSF; TBST; TMB; CL; RMSD; HIS; PBST; TIP3P; RPMI; SH2; SH1; L.donovani
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2024.130670

Cutaneous Leishmaniasis, an infectious disease is globally the most prevalent form of leishmaniasis accounting for approximately 1 million cases every year as per world health organization. Infected individuals develop skin lesion which has been reported to be infiltrated by immune cells and parasite with high sodium accumulation creating hypertonic environment. In our work, we tried to mimic the hypertonic environment in virtual environment to study dynamicity of SHP-1 and NFAT5 along with their interactions through molecular dynamics simulation. We validated the SHP-1 and NFAT5 dynamics in infection and HSD conditions to study the impact of hypertonicity derived NFAT5 mediated response to L.major infection. We also evaluated our therapeutic peptides for their binding to SHP-1 and to form stable complex. Membrane stability with the peptides was analyzed to understand their ability to sustain mammalian membrane. We identified PepA to be a potential candidate to interact with SHP-1. Inhibition of SHP-1 through PepA to discern IL-10 and IL-12 reciprocity may be assessed in future and furnish us with a potential therapeutic molecule. HSD mice exhibited high pro-inflammatory response to L.major infection which resulted in reduced lesion size. Contrary to observations in HSD mice, infection model exhibited low pro-inflammatory response and increased lesion size with high parasite load. Thus, increase in NFAT5 expression and reduced SHP-1 expression may result in disease resolving effect which can be further studied through incorporation of synthetic circuit using PepA to modulate IL-10 and IL-12 reciprocity. Graphical abstract of SHP-1 mediated inhibition of NFAT5 and peptide mediated parasite clearance [Display omitted] •Dynamicity of SHP-1 and NFAT5 studied through simulations and in hypertonic environment.•Efficacy of SHP-1 therapeutic peptides evaluated.•Laid mechanistic insight into IL 10 and IL12 reciprocity.