Mini-Reviews in Medicinal Chemistry, Volume 5, No. 2, 2005
Contents
Drug Efflux Pumps - A Continuing Challenge
Executive Editors: Gerhard F. Ecker / Peter Chiba
Editorial
Recent Methodologies for the Estimation of
N-Octanol/Water Partition Coefficients and their Use in the Prediction of
Membrane Transport Properties of Drugs Pp.127-133
Gilles
Klopman and Hao Zhu
Inhibitors of Multidrug Efflux Transporters:
Their Membrane and Protein Interactions Pp.135-151
A.
Seelig and E. Gatlik-Landwojtowicz
Inhibitors of P-Glycoprotein – Lead
Identification and Optimisation Pp.153-163
Karin
Pleban and Gerhard F. Ecker
Photoaffinity Labeling of P-Glycoprotein Pp.165-172
Michael
Peer, Edina Csaszar, Elisabeth Vorlaufer, Stephan Kopp and Peter Chiba
Multidrug Transporters in Lactic Acid
Bacteria Pp.173-181
P.
Mazurkiewicz, K. Sakamoto, G.J. Poelarends and W.N. Konings
Efflux Transporters and their Clinical
Relevance Pp.183-195
V.
Fischer, H.J. Einolf and D. Cohen
General Reviews
The Impact of Lipophilicity in Drug Research:
A Case Report on ß-Blockers Pp.197-205
Raimund
Mannhold
Effect of Okadaic Acid on Glucose Regulation Pp.207-215
M.C.
Louzao, M.R. Vieytes and L.M. Botana
Focus on Recent Approaches for the
Development of New NO-Donors Pp.217-229
A.
Gasco, R. Fruttero and B. Rolando
Abstracts
[Back to top] Editorial
Gerhard
F. Ecker, Peter Chiba
The problem of
multidrug resistance has gained increasing importance in the fields of tumour
therapy and treatment of bacterial and fungal infections. One of the major
mechanisms responsible for development of multiple drug resistance is
overexpression of drug efflux pumps. These membrane bound, ATP driven transport
proteins efflux a wide variety of natural product toxins and chemotherapeutic
drugs out of cells and give rise to decreased intracellular accumulation of
these compounds. Thus, inhibition of efflux pumps is a versatile approach for
overcoming multiple drug resistance, and several compounds are in clinical
phase III studies. The main target is P-glycoprotein, which is responsible for
MDR in tumour cells, and transport systems in S. aureus, P. aerugiosa
and E. coli. Due to the fact, that 3D-structures of the proteins at
atomic resolution were not available, drug development was performed solely on
basis of ligand based design. However, electron microscopy studies as well as
X-ray structures of three bacterial efflux pumps may open the door to target
based drug design in the near future.
The hot topic
issue will deal with the topic of drug efflux pumps from different
perspectives. The article of Klopman and Zhu present new methodologies for
estimating lipophilicity and their impact on prediction of membrane transport
properties of drugs. Seelig and Gatlik-Landwojtowicz highlight the biophysical
characterisation of inhibitors of efflux pumps and their membrane and protein
interactions. An overview on the approaches used for lead identification and
optimisation for inhibitors of P-glycoprotein is given by Pleban and Ecker.
Peer et al. focus in their article on recent progress in identifying
substrate binding domains of P-glycoprotein by means of photoaffinity labeling.
Analogous multidrug transport systems in lactic acid bacteria are dealt by
Mazurkiewicz et al. Last but not least Fischer et al. give an
overview on the clinical relevance of efflux transporter. These articles will
demonstrate, that, although much progress has been made in the development
of EPIs, we are far away from
understanding the basic principle of drug recognition and transport mechanism
of this class of pumps. These issues will continue to be one of the major tasks
in the field of modulation of drug resistance!
[Back to top] Recent Methodologies for the Estimation of
N-Octanol/Water Partition Coefficients and their Use in the Prediction of
Membrane Transport Properties of Drugs
Gilles
Klopman and Hao Zhu
The lipophilicity
of drug molecules (represented as the logarithm of the n-octanol/water
partition coefficient) often strongly correlates with their pharmacological and
toxic activities. It is therefore, not surprising that there is considerable
interest in developing mathematical models capable to accurately predict their
value for new drug candidates.
In this review,
current major approaches for estimating partition coefficients are described
and some of their advantages and disadvantages are discussed. Recent uses of
these partition coefficient algorithms in the development of membrane transport
models are also discussed.
[Back to top] Inhibitors of Multidrug Efflux Transporters:
Their Membrane and Protein Interactions
A.
Seelig and E. Gatlik-Landwojtowicz
Modulators and
inhibitors of multidrug efflux transporters, like P-glycoprotein, are used to
reduce or inhibit multidrug resistance, MDR, which leads to a failure of the
chemotherapy of e.g. cancers, epilepsy, bacterial, parasitic, and fungal
diseases. Binding and transport of first-, second-, and third-generation
modulators and inhibitors of P-glycoprotein are discussed, taking into account
the properties of the drug (Hbonding potential, dimensions, and pKa
values) as well as the properties of the membrane.
[Back to top] Inhibitors of P-Glycoprotein – Lead
Identification and Optimisation
Karin
Pleban and Gerhard F. Ecker
The membrane bound
drug efflux pump P-glycoprotein (P-gp) transports a wide variety of
functionally and structurally diverse cytotoxic drugs out of tumour cells.
Overexpression of P-glycoprotein is one of the predominant mechanisms
responsible for development of multiple drug resistance in tumour therapy.
Thus, inhibition of P-gp represents a promising approach for treatment of
multidrug resistant tumours. This review highlights concepts for identification
and optimization of new inhibitors of Pglycoprotein.
[Back to top] Photoaffinity Labeling of P-Glycoprotein
Michael
Peer, Edina Csaszar, Elisabeth Vorlaufer, Stephan Kopp and Peter Chiba
The aim of the
present review is to summarize recent progress in identifying substrate binding
domains of P- glycoprotein by photoaffinity labeling. Preferred substrate
binding regions have been identified using a number of photoaffinity ligands,
including anthracyclines, the quinazoline iodoarylazidoprazosine (IAAP),
dihydropyridines, taxanes and propafenones. These studies allowed
identification of protein regions, which are involved in ligand interaction.
[Back to top] Multidrug Transporters in Lactic Acid
Bacteria
P.
Mazurkiewicz, K. Sakamoto, G.J. Poelarends and W.N. Konings
Gram-positive
lactic acid bacteria possess several Multi-Drug Resistance systems (MDRs) that
excrete out of the cell a wide variety of mainly cationic lipophilic cytotoxic
compounds as well as many clinically relevant antibiotics. These MDRs are
either proton/drug antiporters belonging to the major facilitator superfamily
of secondary transporters or ATP-dependent primary transporters belonging to
the ATPbinding cassette superfamily of transport proteins. Here we summarize
the existing data on these MDRs and discuss recent observations that suggest
the use of new strategies in the ongoing battle against drug-resistant
microbial pathogens.
[Back to top] Efflux Transporters and their Clinical
Relevance
V.
Fischer, H.J. Einolf and D. Cohen
It is increasingly
recognized that efflux transporters play an important role, not only in chemo
protection e.g. multi-drug resistance, but also in the absorption,
distribution, and elimination of drugs. The modulation of drug transporters
through inhibition or induction can lead to significant drug-drug interactions
by affecting intestinal absorption, renal secretion, and biliary excretion,
thereby changing the systemic or target tissue exposure of the drug. Few
clinically significant drug interactions that affect efficacy and safety are
due to a single mechanism and there is considerable overlap of substrates,
inhibitors, and inducers of efflux transporters and drug metabolizing enzymes,
such as CYP3A. As well, genetic polymorphisms of efflux transporters have been
correlated with human disease and variability of drug exposure. Accordingly,
this review will discuss drug interactions and suitable probe substrates, as
well as, the clinical relevance of the variability and modulation of efflux
transporters and the exploitation of substrates as diagnostic tools. An update
is given on inhibitors, which clinically reverse drug resistance and minimize
the risk of metabolic interactions.
[Back to top] The Impact of Lipophilicity in Drug Research: A Case Report on
ß-Blockers
Raimund
Mannhold
The key importance
of lipophilicity in bio-studies is discussed for ß-blockers. Examples of their
lipophilicity-dependent pharmacological properties including pharmacokinetic,
pharmacodynamic and clinical aspects are reviewed. Comprehensive lipophilicity
compilations of ß-blockers are lacking so far. LogP calculations with 10
programs for 30 clinically relevant ß-blockers are presented for the first time
in this review.
[Back to top] Effect of Okadaic Acid on Glucose Regulation
M.C.
Louzao, M.R. Vieytes and L.M. Botana
Okadaic acid is
the main toxin responsible for the natural phenomena known as diarrheic
shellfish poisoning (DSP). This toxin is a tumor promoter C38 polyether fatty
acid that contains acidic and hydrophobic moieties and is cyclic. Okadaic acid
is a potent inhibitor of important classes of protein serine/threonine
phosphatases such as protein phosphatase 1 and 2A. The toxin binds in a
hydrophobic groove adjacent to the active site of the protein phosphatases and
interacts with basic residues within the active site. Therefore okadaic acid
causes increases in phosphorylation of proteins that affect a diverse array of
cellular processes. For instance, this toxin modulates metabolic parameters in
intact cells. In this sense it stimulates lipolysis, and inhibits fatty acid
synthesis in adipocytes however increases glucose output and gluconeogenesis in
hepatocytes. Additionally, okadaic acid reaches cytotoxic concentrations in the
intestinal tissues in accordance with the diarrhea. Recent studies suggested
that toxic effects of okadaic acid might be related to modification of
nutrients, ionic and water absorption across the small intestine presumably by
altering the transporter system. The subject of this review is limited to the
effect of okadaic acid on glucose regulation and its cellular as well as
clinical implications.
[Back to top] Focus on Recent Approaches for the Development of New NO-Donors
A.
Gasco, R. Fruttero and B. Rolando
Recent research
developments in the field of NO-donor compounds have concerned conjugation of
NO-donor moieties with antioxidant groups, NO-donor targeting, design of NO-donor
hybrid drugs and of Nodelivery systems. These new approaches are illustrated
and discussed through selected examples.