Synthetic CD4 Peptide Derivatives that Inhibit HIV Infection and Cytopathicity

• Published in: Science (American Association for the Advancement of Science) 1988-08, Vol.241 (4866), p.712-716
• Main Authors: Lifson, Jeffrey D., Hwang, Kou M., Nara, Peter L., Fraser, Blair, Padgett, Mary, Dunlop, Nancy M., Eiden, Lee E.
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; Action of physical and chemical agents; AIDS; AIDS/HIV; Amino Acid Sequence; Amino acid sequencing; Amino acids; Analysis; Antigens, Differentiation, T-Lymphocyte - isolation & purification; Antigens, Differentiation, T-Lymphocyte - pharmacology; Antiviral Agents; Biochemistry; Biological and medical sciences; CD4 Antigens; Cell Fusion; Cell lines; Chromatography, High Pressure Liquid; Fractionation; Fundamental and applied biological sciences. Psychology; Glycoproteins; HIV; HIV (Viruses); HIV - drug effects; HIV - physiology; HIV 1; Human immunodeficiency virus; Immune response; Infections; Lymphocyte Culture Test, Mixed; Mass Spectrometry; Medical research; Microbiology; Molecular Sequence Data; Peptide Fragments - isolation & purification; Peptide Fragments - pharmacology; Protein research; Syncytia; T cells; T lymphocytes; T-Lymphocytes - immunology; T-Lymphocytes - microbiology; Virology; Viruses
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.2969619

Synthetic peptide segments of the CD4 molecule were tested for their ability to inhibit infection of CD4$^{+}$ cells by the human immunodeficiency virus (HIV) and to inhibit HIV-induced cell fusion. A peptide mixture composed of CD4(76-94), and synthesis side products, blocked HIV-induced cell fusion at a nominal concentration of 125 micromolar. Upon high-performance liquid chromatography, the antisyncytial activity of the peptide mixture was found not in the fraction containing the peptide CD4(76-94) itself, but in a side fraction containing derivatized peptide products generated in the automated synthesis. Derivatized deletion and substitution peptides in the region CD4(76-94) were used to demonstrate sequence specificity, a requirement for benzyl derivatization, and a core seven-residue fragment required for antisyncytial activity. A partially purified S-benzyl-CD4(83-94) peptide mixture inhibited HIV-induced cell fusion at a nominal concentration of $\leq $32 micromolar. Derivatized CD4 peptides blocked cell fusion induced by several HIV isolates and by the simian immunodeficiency virus, SIV, and blocked infection in vitro by four HIV-1 isolates with widely variant envelope gene sequences. Purified CD4(83-94) dibenzylated at cysteine 86 and glutamate 87 possessed antisyncytial activity at 125 micromolar. Derivatization may specifically alter the conformation of CD4 holoreceptor peptide fragments, increasing their antiviral efficacy.