Synthesis, metabolic stability and chemotactic activity of peptide T and its analogues.
Acquired immunodeficiency syndrome (AIDS) is initiated by the attachment of the human immunodeficiency virus (HIV) to a surface glycoprotein CD4 present on T4 helper/inducer lymphocytes, monocytes/macrophages and other cells. A simple octapeptide (H-Ala-Ser-Thr-Thr-Thr-Asn-Tyr-Thr-OH, peptide T) seems to inhibit HIV infectivity and to activate human monocyte chemotaxis. In order to study in vitro metabolic stability and structure-activity relationships, peptide T and a number of analogues were prepared and tested on human monocytes by chemotactic assay. Peptide T and the shorter fragments T(3-8)-OH and T(4-8)-OH displayed potent bioactivity (maximal chemotactic activity in the range 10(-11)-10(-10) M). The C-terminal heptapeptide showed a reduction of potency, while further truncations at N-terminus of T(4-8)-OH abolished the biological action. In the octapeptide series, whereas the alpha-amino butyric acid (Abu) substitution for Thr4 was well tolerated, the same "slight" structural change at Thr5 or Thr8 was very detrimental. Finally, [D-Asn6]T(1-8)-OH analogue has low chemotactic activity. All these results indicate that i) the C-terminal pentapeptide is the minimum sequence required for bioactivity, ii) residues 5 to 8 appear to play a crucial biological role, iii) peptide T chemotaxis is mediated, at least in part, through the polar properties of Thr side chains at the critical positions 5 and 8, while the Thr4 does not interfere with biological characteristics of peptides.(ABSTRACT TRUNCATED AT 250 WORDS)
Marastoni
M
M
Department of Pharmaceutical Sciences, University of Ferrara, Italy.
Salvadori
S
S
Balboni
G
G
Spisani
S
S
Gavioli
R
R
Traniello
S
S
Tomatis
R
R
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D002634:Chemotaxis, Leukocyte; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism; D008969:Molecular Sequence Data; D009000:Monocytes / Q000378:metabolism; D015717:Peptide T / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D014269:Trifluoroacetic Acid
D015717:Peptide T; D014269:Trifluoroacetic Acid