Downsizing of an HIV-cell fusion inhibitor, T22 ([Tyr5,12, Lys7]-polyphemusin II), with the maintenance of anti-HIV activity and solution structure.
T22 ([Tyr5,12,Lys7]-polyphemusin II) has been shown to have strong anti-human immunodeficiency virus (HIV) activity comparable to that of 3'-azido-2',3'-dideoxythymidine (AZT). T22, an 18-residue peptide amide, takes an antiparallel beta-sheet structure that is maintained by two disulfide bridges. Herein we synthesized several shortened analogs of T22 in order to search for a more suitable lead compound. A 14-residue analog having one disulfide bridge, TW70 (des-[Cys8,13, Tyr9,12]-[D-Lys10, Pro11]-T22), was found to have highly potent activity comparable to that of T22, and to take an antiparallel beta-sheet structure similar to that of T22. This indicates that the molecular size of T22 can be reduced without loss of activity or significant change in the secondary structure, and that TW70 may represent a novel lead compound. Furthermore, modifying the N-terminal alpha-amino group of TW70 with a fluoresceinthiocarbamoyl group, and the epsilon-amino group of D-Lys8 at the turn portion with a 5-aminopentanoyl group remarkably increased the selectivity index (50% cytotoxic concentration/50% effective concentration).
Tamamura
H
H
Graduate School of Pharmaceutical Sciences, Kyoto University, Japan. tamamura@pharm.kyoto-u.ac.jp or nfujii@pharm.kyoto-u.ac.jp
Waki
M
M
Imai
M
M
Otaka
A
A
Ibuka
T
T
Waki
K
K
Miyamoto
K
K
Matsumoto
A
A
Murakami
T
T
Nakashima
H
H
Yamamoto
N
N
Fujii
N
N
D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides; D002942:Circular Dichroism; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D023181:Antimicrobial Cationic Peptides; D004268:DNA-Binding Proteins; D010455:Peptides; D010456:Peptides, Cyclic; C112118:TW 70; C057636:tachyplesin peptide, Tachypleus tridentatus; C076963:T22 protein, synthetic