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 10‐11‐10‐10M). 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 α‐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. With regard to the enzymic degradation, the in vitro experiments showed the susceptibility of peptide T to rapid metabolism by human or rat plasma (T1/2 = 5.2 min), rat brain (T1/2 = 2.1 min) and kidney (T1/2 = 0.4 min) enzymes. The main metabolic product appears to be the C‐terminal heptapeptide, which retains, in turn, a low enzymatic stability.