Design of a specific peptide against phenolic glycolipid-1 from Mycobacterium leprae and its implications in leprosy bacilli entry

Abstract

BACKGROUND Mycobacterium leprae, the causative agent of Hansen's disease, causes neural damage through the specific interaction between the external phenolic glycolipid-1 (PGL-1) and laminin subunit alpha-2 (LAMA2) from Schwann cells.OBJECTIVE To design a LAMA2-based peptide that targets PGL-1 from M. leprae.METHODS We retrieved the protein sequence of human LAMA2 and designed a specific peptide using the Antimicrobial Peptide Database and physicochemical parameters for antimycobacterial peptide-lipid interactions. We used the AlphaFold2 server to predict its three-dimensional structure, AUTODOCK-VINA for docking, and GROMACS programs for molecular dynamics simulations.FINDINGS We analysed 52 candidate peptides from LAMA2, and subsequent screening resulted in a single 60-mer peptide. The mapped peptide comprises four β-sheets and a random coiled region. This peptide exhibits a 45% hydrophobic ratio, in which one-third covers the same surface. Molecular dynamics simulations show that our predicted peptide is stable in aqueous solution and remains stable upon interaction with PGL-1 binding. In addition, we found that PGL-1 has a preference for one of the two faces of the predicted peptide, which could act as the preferential binding site of PGL-1.MAIN CONCLUSIONS Our LAMA2-based peptide targeting PGL-1 might have the potential to specifically block this key molecule, suggesting that the preferential region of the peptide is involved in the initial contact during the attachment of leprosy bacilli to Schwann cells.

Mycobacterium leprae’s Infective Capacity Is Associated with Activation of Genes Involved in PGL-I Biosynthesis in a Schwann Cells Infection Model

“…The ability of M. leprae to bind through a specific interaction of PGL-I with the alpha-2 subunit of human laminin (LAMA2) promotes the attachment of the bacillus to the basal lamina of the SCs. This allows the internalization of the pathogen [12,17,47]. In addition, M. leprae has developed PGL-I production to evade innate immunity and establish longterm residence in the host [16].…”

“…The PGL-I biosynthetic pathway involves more than 20 enzymatic steps; the lipid core formation is typical in all PGL-containing mycobacteria, but the saccharide portion of PGL is specific to each mycobacteria [16]. The trisaccharide position of PGL-I has been proposed to promote SC invasion and thus may be responsible for the unique ability of M. leprae to invade peripheral nerves [5,12,17].…”