Journal
BIOCHEMISTRY
Volume 44, Issue 12, Pages 4648-4655Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bi0477081
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Funding
- NCCIH NIH HHS [R01 AT001383-02, R01-AT01383, R01 AT001383-01A2, R01 AT001383-03, R01 AT001383] Funding Source: Medline
- NIAID NIH HHS [R01 AI031343-06, R01 AI031343-03, R01 AI031343-03S1] Funding Source: Medline
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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., Kuna, 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. HLI 8 and HL9 are potent inhibitors of HIV-1 infection and replication with EC50S 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, stres;s, TGF beta, p53, NF kappa B, protein kinase C and hedgehog signaling.
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