Oligonucleotide transition state analogues of saporin L3.
Ribosome inactivating proteins (RIPs) are among the most toxic agents known. More than a dozen clinical trials against refractory cancers have been initiated using modified RIPs with impressive results. However, dose-limiting toxicity due to vascular leak syndrome limits success of the therapy. We have previously reported some tight-binding transition state analogues of Saporin L3 that mimic small oligonucleotide substrates in which the susceptible adenosine has been replaced by a 9-deazaadenyl hydroxypyrrolidinol derivative. They provide the first step in the development of rescue agents to prevent Saporin L3 toxicity on non-targeted cells. Here we report the synthesis, using solution phase chemistry, of these and a larger group of transition state analogues. They were tested for inhibition against Saporin L3 giving Kivalues as low as 3.3 nM and indicating the structural requirements for inhibition.
The Ferrier Institute, Victoria University of Wellington, 69 Gracefield Rd, Lower Hutt 5010, New Zealand. Electronic address: jennifer.mason@vuw.ac.nz.
Jennifer M
JM
Mason
Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA.
Hongling
H
Yuan
The Ferrier Institute, Victoria University of Wellington, 69 Gracefield Rd, Lower Hutt 5010, New Zealand.
Gary B
GB
Evans
The Ferrier Institute, Victoria University of Wellington, 69 Gracefield Rd, Lower Hutt 5010, New Zealand.
Peter C
PC
Tyler
Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA.
Quan
Q
Du
Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA.
Vern L
VL
Schramm
D001483:Base Sequence; D040761:Biomimetic Materials / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D009841:Oligonucleotides / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology*; D011487:Protein Conformation; D012313:RNA / Q000235:genetics / Q000378:metabolism; D054789:Ribosome Inactivating Proteins, Type 1 / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D000076985:Saporins
D009841:Oligonucleotides; D054789:Ribosome Inactivating Proteins, Type 1; D012313:RNA; D000076985:Saporins
Aza-sugar; Oligonucleotide; Ribosome inactivating protein; Saporin; Transition state inhibitor