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, which efficiently inhibits infection of target cells by T-cell line-tropic strains of HIV-1 (X4-HIV-1) through its specific binding to a chemokine receptor, 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. On the other hand, a C-terminally amidated analogue of T140, TZ14004, has been 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 strong 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 seemed to be a suitable balance between activity and cytotoxicity. In this study, we have conducted a double-L-citrulline (Cit)-scanning study on TZ14004 based on the C-terminally amidated form in due consideration of the total net charges in the whole molecule to find novel effective CXCR4 inhibitors, 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 indexes (SIs) and complete stability in feline serum.
Tamamura
H
H
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, 606-8501, Kyoto, Japan. tamamura@pharm.kyoto-u.ac.jp
Omagari
A
A
Hiramatsu
K
K
Gotoh
K
K
Kanamoto
T
T
Xu
Y
Y
Kodama
E
E
Matsuoka
M
M
Hattori
T
T
Yamamoto
N
N
Nakashima
H
H
Otaka
A
A
Fujii
N
N
D000818:Animals; D019380:Anti-HIV Agents / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D002415:Cats; D002470:Cell Survival / Q000187:drug effects; D002942:Circular Dichroism; D002956:Citrulline / Q000737:chemistry*; D004355:Drug Stability; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*
D019380:Anti-HIV Agents; D009842:Oligopeptides; D010455:Peptides; D019718:Receptors, CXCR4; D002956:Citrulline; C116977:T140 peptide