Catania TTO - Fondazione IRCCS Ca` Granda

“Synthetic melanocortins with
antimicrobial activity”
The problem
The widespread use of antibiotics has caused a growing problem of antimicrobial
resistance in the community and in hospital settings. Both fungal and bacterial resistance
to current therapies are observed, particularly in immunocompromised patients.
Therefore, the need for alternative antimicrobial agents is impelling.
State of the art: Synthetic melanocortins as new drugs
The melanocortins are endogenous peptides that exert pleiotropic effects on the host. One
of these molecules, α-melanocyte stimulating hormone (α-MSH), has anti-inflammatory
and antimicrobial action. However, the 13 amino acid natural peptide has a short half-life,
is not selective for individual melanocortin receptors, and, therefore, is unsuitable for
clinical use. Chemically stable synthetic derivatives, with more selective activity are being
currently developed by pharmaceutical industry. Instances are: AP214 for renal disorders
(Abbott); Afamelanotide to prevent photosensitivity and in treatment of erythropoietic
protoporphyria (Clinuvel); melanocortin-4 (MC-4) receptor agonists for obesity, diabetes
and related metabolic syndrome (Palatin Technologies).
Based on recent observations, synthetic melanocortins could likewise form the
basis for novel antimicrobial therapies.
The solution
Structure-activity relation (SAR) studies on α-MSH-derived sequences were performed to
design synthetic molecules with enhanced potency and broad spectrum of antimicrobial
activity. Replacement of Gly10 in [DNal(2’)-7, Phe-12]-α-MSH(6-13) with several
conventional and unconventional amino acids with different degrees of conformational
rigidity allowed discovery of two derivatives with potent antimicrobial activity. These
synthetic peptides had anti-Candida properties, including azole-resistant Candida strains,
and exerted killing activity against bacterial strains including gram-positive and gramnegative organisms.
Advantages
These small, 8 amino acid antimicrobial peptides could represent novel therapeutic agents
to treat infective disorders.
Advantages of these new synthetic compounds are:
1. Broad spectrum of activity that includes yeasts and gram-positive and gramnegative bacteria;
2. Concomitant anti-inflammatory action.
Stage of Development- Research Data
The novel compounds exert killing activity against fungi such as Candida albicans,
including azole resistant strains, C. glabrata, and C. krusei; against gram-negative bacteria
such as Acinetobacter baumani, Escherichia coli, Pseudomonas aeruginosa,
Pseudomonas syringae pv tabaci; gram-positive bacteria including Bacillus megaterium,
Staphylococcus aureus, and Staphylococcus epidermidis.
Therapeutic development
Synthetic melanocortins with antimicrobial effects could be novel agents to treat infections.
They are small peptides, chemically stable, that could form the basis for effective
therapies.
Examples of therapeutic uses are:
a) local
- Dermatological infections marked by concomitant presence of gram-positive and gramnegative bacteria and fungi such as pressure sores, burns and scalds, and many other
conditions.
- Dental and periodontal diseases;
- Vaginal infections
b) systemic
-Immunocompromised host with multiple resistance to conventional antibiotics.
Competitive advantage
Broad spectrum of antimicrobial action that includes yeasts and bacteria and low toxicity.
Concomitant anti-inflammatory action.
Possible routes of administration
• Incorporation in gel, ointment, or cream for topical administration in dermatological
infections;
• Mouthwash for dental or periodontal diseases;
• Incorporation in transdermal delivery systems for systemic administration;
• Intravenous administration.
References
1) Cutuli MG, Cristiani S, Lipton, JM, Catania A. J Leukoc Biol 67:233-9, 2000.
2) Grieco P, Rossi C, Colombo G, Gatti S, Novellino E, Lipton JM, Catania A.
J Med Chem, 46: 850-855, 2003
3) Grieco P, Rossi C, Gatti S, Colombo G, Carlin A, Novellino E, Lama T, Lipton JM,
Catania A. J Med Chem 48: 1384-1388 , 2005
4) Catania A, Colombo G, Rossi C, Carlin A, Sordi A, Lonati C, Turcatti F, Leonardi P,
Grieco P, Gatti S.. The Scientific World Journal 6: 1241-1246, 2006
5) Carotenuto A, Saviello MR, Auriemma L, Campiglia P, Catania A, Novellino E, Grieco P.
Chem Biol Drug Des 69:68-74, 2007
6) Grieco P, Carotenuto A, Auriemma L, Limatola L, Di Maro S, Merlino F, Mangoni ML,
Vincenzo Luca V, Di Grazia A, Gatti S, Campiglia P, Gomez-Monterrey I, Novellino E and
Anna Catania A, PLOS ONE 8 (4): e61614, 2013
Intellectual Property
An international patent application has been published as WO 2010/081492.
Granted patent in Europe, USA, Japan. Pending counterparts in Canada, Israel and India.
Applicants
The Fondazione IRCCS “CA’ Granda - Ospedale Maggiore Policlinico” is an Italian public
corporation committed to healthcare and translational medicine. Moreover, it is a centre of
excellence for research in the field of immunotheraphy, acute and chronic respiratory
diseases, rare diseases and regenerative medicine.
Inventors
Anna Catania is the senior scientific researcher, coordinator and supervisor of all the
experimental works and R&D director at Center for Preclinical Investigation Fondazione
IRCCS “CA’ Granda- Ospedale Maggiore Policlinico” in Milan (Italy). She is the principal
investigator in a number of national and international research programs related to basic
and clinical research on melanocortins, partly performed at the Southwestern Medical
Center at Dallas. She is the author of more than 100 scientific publications focused on
natural and synthetic melanocortins and their receptors in international journals. She is the
Editor of the book Melanocortins: Multiple Actions and Therapeutic Potential, Springer,
2010.
Paolo Grieco is Professor of Medicinal Chemistry at the Dept. of Pharmaceutical and
Toxicological Chemistry, University of Naples Federico II.
He is the author of more than 150 scientific publications in international journals, mainly
focused on peptide and peptidomimetic chemistry. His research activity is addressed to
chemistry and medicinal chemistry of peptides, peptidomimetics, small molecules ligands
receptors and, in particular to the chemistry of melanocortins.
He is a member of the Italian Chemical Society, European Peptide Society and American
Peptide Society.
For further information:
Technology Transfer Office
Laura Spinardi, PhD
[email protected]