title: Structural and functional modeling of human lysozyme reveals a unique nonapeptide, HL9, with anti-HIV activity.
abstract: We previously reported that lysozyme accounts for anti-HIV activity associated with the beta-core fraction of human chorionic gonadotropin [Lee-Huang, S., Huang, P. L., Sun, Y., Kung, H. F., Blithe, D. L. & Chen, H. C. (1999) Proc Natl Acad Sci U S A 96, 2678-81]. To define the structural and sequence requirements for anti-HIV activity, we carried out peptide fragmentation and activity mapping of human lysozyme. We identified two peptides that consist of 18 and 9 amino acids of human lysozyme (HL18 and HL9), corresponding to residues 98-115 and 107-115. HL18 and HL9 are potent inhibitors of HIV-1 infection and replication with EC(50)s of 50 to 55 nM, comparable to intact lysozyme. Scrambling the sequence or substitution of key arginine or tryptophan residues results in loss of antiviral activity. HL9, with the sequence RAWVAWRNR, is the smallest peptide we identified with full anti-HIV activity. It forms a pocket with its basic residues on the surface of the molecule. HL9 exists as an alpha-helix in native human lysozyme, in a region of the protein distinct from the muramidase catalytic site. Monte Carlo peptide folding energy minimizing simulation modeling and CD studies indicate that helical propensity does not correlate with antiviral activity. HL9 blocks HIV-1 viral entrance and replication, and modulates gene expression of HIV-infected cells, affecting pathways involved in survival, stress, TGFbeta, p53, NFkappaB, protein kinase C and hedgehog signaling.
authors.affiliation: Department of Biochemistry, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Lee-Huang
authors.forename: Vladimir
authors.initials: V
authors.lastname: Maiorov
authors.forename: Philip L
authors.initials: PL
authors.lastname: Huang
authors.forename: Angela
authors.initials: A
authors.lastname: Ng
authors.forename: Hee Chul
authors.initials: HC
authors.lastname: Lee
authors.forename: Young-Tae
authors.initials: YT
authors.lastname: Chang
authors.forename: Neville
authors.initials: N
authors.lastname: Kallenbach
authors.forename: Paul L
authors.initials: PL
authors.lastname: Huang
authors.forename: Hao-Chia
authors.initials: HC
authors.lastname: Chen
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D002460:Cell Line; D002942:Circular Dichroism; D006678:HIV / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D006868:Hydrolysis; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009113:Muramidase / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D009842:Oligopeptides / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology
chemical_list: D019380:Anti-HIV Agents; D009842:Oligopeptides; D009113:Muramidase