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

Area of Science:

• Infectious Diseases
• Immunology
• Computational Biology

Background:

• Cutaneous leishmaniasis is a prevalent infectious disease causing skin lesions.
• Lesions exhibit immune cell infiltration, parasite presence, and a hypertonic environment due to high sodium accumulation.
• The role of SHP-1 and NFAT5 in hypertonicity-induced responses during Leishmania major infection requires further elucidation.

Purpose of the Study:

• To simulate the hypertonic environment of cutaneous leishmaniasis lesions in a virtual setting.
• To investigate the molecular dynamics and interactions of SHP-1 and NFAT5 under hypertonic stress and L. major infection.
• To evaluate therapeutic peptides for their binding affinity to SHP-1 and their potential to modulate immune responses.

Main Methods:

• Molecular dynamics simulations were employed to study the behavior of SHP-1 and NFAT5.
• The dynamics of SHP-1 and NFAT5 were validated in both infected and high-salt diet (HSD) conditions.
• Therapeutic peptides were assessed for their binding to SHP-1, complex stability, and membrane interaction.

Main Results:

• Hypertonicity significantly impacts NFAT5-mediated responses to L. major infection.
• Peptide PepA demonstrated potential for interacting with and inhibiting SHP-1.
• HSD mice showed a reduced lesion size with a high pro-inflammatory response to L. major infection, unlike the infection model.

Conclusions:

• Increased NFAT5 expression and reduced SHP-1 expression may contribute to a disease-resolving effect in cutaneous leishmaniasis.
• PepA shows promise as a therapeutic molecule for inhibiting SHP-1, potentially modulating IL-10 and IL-12.
• Further research involving synthetic circuits with PepA could offer a novel therapeutic strategy for leishmaniasis.