9q9v | pdb_00009q9v
Crystal structure of Borrelia burgdorferi BB0238-BB0323 complex
Structural highlights
Publication Abstract from PubMedBorrelia burgdorferi, one of the most prevalent tick-borne pathogens, can cause a complex and multisystem illness called Lyme disease, where there has been an unmet need for novel therapeutic or preventive strategies. We previously identified an essential protein-protein interaction (PPI) event in B. burgdorferi involving two unique proteins, BB0323 and BB0238; herein, we show that this PPI is indispensable for long-term borrelial survival in mammals and explore its potential as a novel target for small molecule therapeutics. Using X-ray crystallography, we solved the structure of the BB0238-BB0323 complex and identified the hotspot residues that form the biomolecular PPI interface area of ~1000 square Angstroms. We then performed quantitative high-throughput drug screens of 62,740 diverse small molecules utilizing an amplified luminescent proximity homogeneous assay linked immunosorbent assay (AlphaLISA). Following a comprehensive pipeline to confirm small molecule hits, we short-listed three distinct PPI inhibitors of BB0238-BB0323. One of these inhibitors, called lomibuvir (VX-222, VCH-222), displayed robust PPI inhibition inside B. burgdorferi cells and was shown to affect pathogen persistence in a tick-borne murine model of Lyme disease. Our study highlights targeted PPI disruption as a new therapeutic strategy against B. burgdorferi and may foster future antimicrobial discovery efforts to resolve clinical complications associated with Lyme disease. Targeting of interaction between BB0323-BB0238 informs new paradigms in Lyme disease therapeutics.,Bista S, Brangulis K, Bhattachan B, Foor SD, Ronzetti MH, Jain S, Miller J, Subramanion JL, Kitsou C, Rana VS, Rai G, Zakharov AV, Simeonov A, Baljinnyam B, Pal U PLoS Pathog. 2026 Jan 2;22(1):e1013805. doi: 10.1371/journal.ppat.1013805. , eCollection 2026 Jan. PMID:41481600[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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