Development of specific CXCR4 inhibitors possessing high selectivity indexes as well as complete stability in serum based on an anti-HIV peptide T140

We previously reported a truncated polyphemusin peptide analogue, T140, whi ch efficiently inhibits infection of target cells by T-cell line-tropic str ains of HIV-1 (X4-HIV-1) through its specific binding to a chemokine recept or. CXCR4. We have found that T140 is not stable in feline serum due to the cleavage of the C-terminal Arg,(14) indispensable for anti-HIV activity. O n the other hand, a C-terminally amidated analogue of T140, TZ14004, has be en found to be completely stable in incubation in the serum for 2 days. The C-terminal amide is thought to be needed for stability in serum. However. TZ14004 does not have fairly strong anti-HIV activity, but has relatively s trong cytotoxicity, probably due to an increase by + 1 charge from total 7 charges of T140. In our previous study, the number of total + 6 charges s eemed to be a suitable balance between activity and cytotoxicity. In this s tudy, we have conducted a double-L-citrulline (Cit)-scanning study on TZ140 04 based on the C-terminally amidated form in due consideration of the tota l net charges in the whole molecule to find novel effective CXCR4 inhibitor s, TN14003 ([Cit(6)]-T140 with the C-terminal amide) and TC14012 ([Cit(6), D-Cit(8)]-T140 with the C-terminal amide), which possess high selectivity i ndexes (SIs) and complete stability in feline serum. (C) 2001 Elsevier Scie nce Ltd. All rights reserved.