Author/Editor		Kem, William R
Title		Ion channel toxins as molecular models for the design of new drugs
Translated title		Toksini, ki delujejo na ionske kanalčke, kot molekularni modeli za načrtovanje novih zdravil
Type		članek
Source		Acta Biol Slov
Vol. and No.		Letnik 43, št. 1-2
Publication year		2000
Volume		str. 125-9
Language		eng
Abstract		Naturally occurring toxins possessing high affinity and selectivity for particular cell receptors, besides being excellent molecular probes in biomedical research, can also serve as lead compounds for drug design. Manipulation of their structures can often reduce their toxicity without abolishing therapeutically useful effects. Such toxins have already been discovered in most cases. Two examples of this drug development approach will be presented: (1) a nemertine worm toxin (the bicyclic alkaloid anabascine), when derivatized with an aromatic aldehyde, yielded a compound which selectively stimulates brain alpha7 nicotinic receptors and enhances cognition. DMXBA (GTS- 21) also displays neuroprotective activily and is much less toxic than nicotine. While some nicotinic receptors disappear as Alzheimer's disease progresses, alpha7 rcceptors are not greatly affected and therefore can continue to serve as a CNS drug target. It was recently demonstrated that the primary metabolites of DMXBA are even more potent alpha7 agonists than the parent compound. (2) A new K channel peptide toxin, ShK, found in the sea anemone Stichodacryla helianthus has been synthesized by solid-phase melhods. The NMR-derived solution structure of this 35 residue peptide contains a scaffold consisting of two short alpha-helices separated by a beta turn, in contrast to the beta-sheet scaffold present in the scorpion toxin charbydoloxin which interacts with the same external site in certain voltage- and Ca-gated K channels. The homomeric Kv1.3 channel is largely confined lo the T-lymphocyte cell surface. Toxin blockade of this channel inhibits proliferation of these cells in vitro and the development of a delayed type hypersensitivity reaction in vivo. (Abstract truncated at 2000 characters).
Summary		Naravne toksine, ki so specifično selektivni za določene tipe celičnih receptorjev, lahko uporabljamo kot molekularna orodja v biomedicinskih raziskavah pa tudi kot vodilne spojine za načrtovanje in razvoj novih zdravil. S spremembami zgradbe teh snovi lahko zmanjšamo toksičnost ne da bi se ob tem zmanjšala njihova terapevtska uporabnost. Poznamo kar nekaj takih toksinov, v tem delu bomo predstavili dva primera. (1) Toksin iz nitkarja (biciklicni alkaloid anabaseine), ki ga obdelamo z aromatskim aldehidom, tako da dobimo spojino imenovano GTS-21 (primarni metabolit DMXBA). Ta spojina selektivno stimulira možganske alfa7 nikotinske receptorje in tako izboljša pomnenje. GTS-21 deluje tudi nevro-protektivno in je mnogo manj toksična od nikotina. Za Alzheimerjevo bolezen je značilno, da se ob napredovanju bolezni zmanjšuje število nekaterih nikotinskih receptorjev, medtem ko ostaja število alfa7 receptorjev nespremenjeno. Zaradi tega so alfa7 receptorji primerna tarča za farmake, ki stimulirajo delovanje centralnega živčevja. Pred kratkim se je pokazalo, da je primarni metabolit DMXBA celo močnejši agonist receptorjev alfa7 kot osnovna spojina. (2) ShK iz morske vetrnice Stichodactyla helianthus je novi peptidni inhibitor homomernih kalijevih kanalčkov, ki so ga dobili z peptidno sintezo. Osnovni skelet tega peptida iz 35 aminokislin, ki so jo določili s pomočjo NMR, sestavljata dva kratka odseka a-vijačnice ločena z b-obratom. To je v nasprotju z ogrodjem škorpijonskega karibdotoksina, katerega osnovo predstavlja b-struktura. Ta toksin se veže na od kalcija odvisne kalijeve kanalčke, z ShK pa si deli tudi isto vezavno mesto na nekaterih napetostno odvisnih kalijevih kanalčkih. Napetostno odvisen kalijev kanalček tipa Kv 1.3 je glavni kanalček limfocitov T. Inhibicija teh kanalčkov prepreči delitev limfocitov in vitro pa tudi zakasnjeno občutljivostno reakcijo in vivo. (Izvleček skrajšan na 2000 znakov).
Descriptors		ALZHEIMER'S DISEASE POTASSIUM CHANNELS IMMUNOSUPPRESSIVE AGENTS DRUGS, INVESTIGATIONAL MODELS, MOLECULAR DRUG INDUSTRY