Effective lowly cytotoxic analogs of an HIV-cell fusion inhibitor, T22 ([Tyr5,12, Lys7]-polyphemusin II)

Bioorganic & Medicinal Chemistry
Hirokazu TamamuraN Fujii

Abstract

A tachyplesin peptide analog, T22 ([Tyr5,12, Lys7]-polyphemusin II), and its shortened congener, TW70 (des-[Cys8,13, Tyr9,12]-[D-Lys10, Pro11]-T22) have strong anti-human immunodeficiency virus (HIV) activity, comparable to that of 3'-azido-2', 3'-dideoxythymidine (AZT). T22 and TW70 are extremely basic peptides, containing 5 Arg residues and 3 Lys residues. The number of positive charges might be related in part to high collateral cytotoxicities of T22 and TW70. Here we have synthesized several analogs, in which the number of positive charges has been reduced through amino acid substitutions using Glu or L-citrulline. As a result, several effective compounds have been found which possess higher selectivity indexes (SIs, 50% cytotoxic concentration/50% effective concentration) than those of T22 and TW70. Higher SIs were attributed mainly to a decrease in cytotoxicity.

References

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Citations

Sep 13, 2011·Journal of Medicinal Chemistry·Oliver DemmerHorst Kessler
Nov 19, 2002·Antimicrobial Agents and Chemotherapy·Valery FikkertMyriam Witvrouw
Dec 1, 2001·Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan·H Tamamura
May 10, 2011·Cellular and Molecular Life Sciences : CMLS·W Todd PenberthyAlexander M Cole
Dec 17, 2008·Seminars in Cancer Biology·Hyunsuk ShimNobutaka Fujii
Jun 15, 2005·Scandinavian Journal of Immunology·C D MilneC J Paige
Jan 31, 2003·Expert Opinion on Investigational Drugs·Nobutaka FujiiHirokazu Tamamura
May 20, 1999·Biopolymers·D Andreu, L Rivas
Sep 25, 2019·Molecular Pharmacology·Ilze AdlereRob Leurs
Dec 28, 2019·Advanced Materials·María Virtudes CéspedesAntonio Villaverde
Feb 6, 2020·Experimental Biology and Medicine·Chaozai ZhangJing An
Apr 21, 2012·Organic & Biomolecular Chemistry·Shinya Oishi, Nobutaka Fujii
Jul 23, 2011·ChemMedChem·Oliver DemmerHans-Jürgen Wester
Jan 27, 1999·Biochemical and Biophysical Research Communications·H TamamuraN Fujii
Nov 9, 2021·Drug Delivery·Patricia ÁlamoAntonio Villaverde

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