IMMUNOMODULATING ACTIVITY OF ANALOGS OF NONINFLAMMATORY FRAGMENT-163-171 OF HUMAN INTERLEUKIN-1-BETA

The synthetic nonapeptide Val-Gln-Gly-Glu-Glu-Ser-Asn-Asp-Lys correspo nding to the amino acid sequence 163-171 of human interleukin-1 beta ( IL-1 beta) has been reported to retain considerable immunostimulatory activity of the native protein without the induction of the inflammato ry or pyrogenic responses. Two lipophilic derivatives of this nonapept ide, one having a lauroyl residue (1) and the other having a palmitoyl residue (2) at the N-terminus of the peptide, and a more stable analo g carrying D-Val residue at position 1 of the peptide (3) were synthes ized with a view to find out if these structural modifications had a f avorable effect on in vitro mouse thymocyte proliferation and IL-1 dep endent inhibition of A375 cells. We have found that analogs (1) and (2 ) are active in both the tests like the parent nonapeptide. The lipoph ilic analog (2) is in fact, effective at a lower dose as compared to t he parent nonapeptide in mouse thymocyte proliferation assay. Although the analog (3) has the ability to inhibit A375 cells, it does not sti mulate mouse thymocyte proliferation in vitro. The IL-1 beta fragment (163-171) and the analog (2) were further compared for their effects o n pyrogenicity, blood glucose level, acute phase response and radiopro tection. Unlike IL-1 beta, its fragment (163-171) and the analog (2) d o not induce pyrogenicity and any of the acute phase related changes s uch as the increase in C-reactive protein and hypoglycemia following t heir administration in Balb/c mice. We have found that 40% of animals treated with analog (2) survive more than 21 days after lethal irradia tion as compared to 20% survivors in groups treated with recombinant I L-1 beta or its nonapeptide fragment (163-171), under conditions when all the control animals died within 10 days. This study may help in de signing small peptides which may be more effective and stable. (C) 199 8 Elsevier Science B.V.