The carbonic anhydrases (CAs, EC 4.2.1.1) are widespread enzymes all over
the phylogenetic tree, form very simple organisms, such as bacteria and
microscopic fungi or protosoa, to plants and animals. They constitute
interesting targets for the design of pharmacological agents useful in the
treatment or prevention of a variety of disorders such as glaucoma,
acid-base disequilibria, epilepsy, and various other neuromuscular
diseases, altitude sickness, edema, and obesity. They have been used for
many years as diuretics.
CA inhibitors (CAIs) were recently shown to be useful in the management
(imaging and treatment) of hypoxic tumors, since at least two CA isozymes
of the 16 presently known in mammals, i.e., CA IX and XII, are
predominantly found in tumor cells and are lacking from normal tissues. The
involvement of these enzymes, which catalyze the simplest physiological
reaction, CO2 hydration to bicarbonate and a proton, in many
physiological/pathological processes—as well as the fact that
generally different isoforms of the 16 mentioned above are involved in such
particular processes—allows for the development of diverse medicinal
chemistry applications of their inhibitors.
Thus, CA IX and XII are the targets for the development of novel antitumor
therapies, CA II and XII for the development of antiglaucoma drugs, CA Va
and CA Vb for the design of new anti-obesity agents, CA VII for the
development of anticonvulsant/antiepileptic drugs; whereas non-vertebrate
CAs, such as for example the a-CA present in Plasmodium falciparum
may lead to novel types of antimalaria drugs.
Recently cloned and purified/characterized were many such enzymes
(generally belonging to the ß-CA class) from many pathogenic
organisms such as the bacteria Mycobacterium tuberculosis and
Helicobacter pylori, or the fungi Candida albicans and
Cryptococcus neoformans. Inhibition of these enzymes may lead to a
new generation of antiinfectives.
Activation of different CA isoforms was mainly investigated by our group,
and has recently been shown to constitute a novel therapeutic approach for
the enhancement of synaptic efficacy, which may constitute an excellent
means for the treatment of Alzheimer's disease, aging, and other conditions
in need of achieving spatial learning and memory therapy.
Thus, one may modulate the activity of CAs either by inhibiting or by
activating these enzymes with specific agents, the mechanisms of actions
which have begun to be ultimately understood in greater detail.
Furthermore, I predict that many other families of CAs will be discovered
in the future in addition to the five such families presently known (the
a-z -CAs), since these enzymes deal with a critical compound—carbon
dioxide—important for biosynthetic processes involving one carbon
atom, and which probably has already played important roles in the
primordial stages of life on earth.
Nowadays, over-production of carbon dioxide in the atmosphere and its
involvement in the global warming processes might also be dealt with by
using some of the enzymes which efficiently convert this pollutant to
bicarbonate, which is non-toxic, water soluble, and has no global warming
effects.
It should be mentioned that over the last few years we have also reported
the X-ray crystal data of many CAs with various drugs, such as, among
others, the diuretics indapamide, chlorthalidone, furosemide, and
triflumethiazide (shown in the Figure).
Does it describe a new discovery, methodology, or
synthesis of knowledge?
This is a review article, presenting the state of the art in the field of
CA inhibitors and activators, as well as their applications in therapy. It
presents diverse methodologies useful in the drug design of different
pharmacological agents based on CAIs and CA activators (CAAs). This paper
represents a thorough review of all these novel applications of CAIs/CAAs,
updated with the latest developments in the field.
Could you summarize the significance of your paper
in layman's terms?
Compounds belonging to the CAIs may lead to better drugs useful to treat
glaucoma, a chronic eye disease leading to blindness, which is rather
diffused, and for which no optimal cure is available at this moment. On the
other hand, since several CAs are predominantly found in tumors—and
more precisely in hypoxic tumors—compounds of this type seem very
promising for discovering novel antitumor therapies as well as for imaging
purposes of diverse cancers.
Finally, some CAIs seem to be useful for developing novel anti-obesity
drugs. Thus, at least three conditions in need of pharmacological
treatment, i.e., glaucoma, cancer, and obesity, may benefit from drugs
belonging to this class. It should also be stressed that the isozymes
responsible for the three pathologies examined here are different: CA II
and XII for glaucoma, CA IX and XII for cancer and CA V for anti-obesity
drugs.
The CAAs, on the other hand, may lead to the development of agents useful
in the treatment of Alzheimer's disease or other conditions in need of
achieving spatial learning and memory therapy. The important progress done
ultimately in deciphering the structure, catalytic and inhibition
mechanisms of CAs from pathogenic organisms, may lead to the development of
antifungal or antibacterial drugs possessing a new mechanism of action.
How did you become involved in this
research?
My interest in CA research dates back to 1987. Since then, our group at the
University of Florence, in Italy, was involved in several research projects
on CA inhibitors and activators, financed either by the European Union or
from private drug companies. Our group has achieved international
recognition due to the fact that many important discoveries related to the
field have been performed here. As a consequence, our laboratory is
financed by the EU as well as by some of the most important drug companies
interested in the development of novel therapies based on such compounds.
We are currently participating in several such programs, aimed at the
development of anti-glaucoma, anti-cancer, anti-obesity, and anti-infective
drugs, as well as research leading to a better understanding of the
interactions of such compounds with enzymes, which we study using a variety
of modern methods. We are collaborating for such purposes with many
excellent research groups in Europe, the USA, Japan, Australia, and Turkey,
a factor which may also help explain our successes and the priorities in CA
research as reviewed in the paper.
Dr. Claudiu T. Supuran
Università di Firenze
Dipartimento di Chimica
Laboratorio di Chimica Bioinorganica
Firenze, Italy
Superposition of X-ray crsytal structures of the human carbonic
anhydrase II (hCA II) – clortalidone (yellow), hCA II –
indapamide (wheat), hCA II – triclorometiazide (sky) and hCA II
– furosemide (magenta) adducts. The histidine ligands coordinating
the zinc ion (violet sphere) and protein backbones (green) in all four
complexes are entirely superposable. The four compounds are widely used
diuretic drugs.(cf. Temperini et al.,
Bioorg.Med. Chem Lett. 2009, 17,
1214-1221).