UNIVERSITÀ DI PISA

COMPOUNDS WITH A BENZO [A]CARBAZOLE STRUCTURE FOR USE IN THE PREVENTION AND/OR TREATMENT OF INFECTIOUS DISEASES

The invention relates to the use of compounds with a benzo[a]carbazole structure of formula (I) in the prevention and/or treatment of infectious diseases caused by pathogens. The compounds according to the invention act directly against the infected host cell in the patient. These do not exhibit any antibacterial activity when tested directly on culture of bacteria. They do not act on the infecting agent but on the infected host cells, and should not produce the effects of resistance to the treatment typical of the various classes of antibacterial, antiviral, antifungal and antiprotozoal agents.

Patent Status

GRANTED

Priority Number

102021000020582

Priority Date

07/09/2017

License

ITALY

Market

The recent SARS-CoV 2 pandemic crisis has highlighted the need for new therapeutic treatments. More generally the therapeutic problems linked to the selection, mutation and resistance have been known for some time. For this reason, study and development of new drugs or vaccines capable of overcoming these problems and being useful in endemic and/or pandemic situations are continuously needed. Currently, anti-infective drugs represent a very large market size of US $ 1,350,961 Million in 2022 with an expected increase to US $ 1,640,196 Million in 2028. This market increase, in the next 5 years period, represent an interesting CAGR (Compounded Average Growth Rate) of about 3,5% where the major players will be Merck, GSK, Gilead, Novartis and Pfitzer (these are sorted in no particular order).

Problem

Just considering bacteria, these infectious agents cause millions of casualties each year, and the spreading of antibiotic multi-resistance is recognized as a major global health concern and a pressing social challenge. Development of new antibiotics with novel modes of action and innovative strategies to efficiently fight bacterial infections are urgently needed. The World Health Organization (WHO) has generated a global priority list of pathogens urgently needing new antibiotics. E.g. Group A Streptococcus, Pseudomonas aeruginosa, Cholera and Mycobacterium tuberculosis were listed by WHO as the most critical pathogens for which new antibiotics are urgently needed.
Looking more broadly at the anti-infectious problem, WHO reports as emergency risks to public health, in various countries of the world, in addition to the well-known SARS Corona virus in its continuous mutations, viruses such as Marburg, Nipah, Ebola, Avian influenza A(H5), Poliovirus type2, Yellow fever, Dengue and other risks linked to protozoans such as Malaria for example.
All these epidemic parasites need of new therapeutic treatment with new drugs and, when it is possible, new vaccines. The overall costs for health care worldwide have become exponential and almost unsustainable.
Therefore, finding new classes of anti-infectives with new mechanism of action which could cure infections by reducing the risks associated with the onset of selection, mutation and resistance phenomena in the pathogens have become essential and strategic. This in order to make pharmaceutical expenses sustainable and to allow safe treatment of large populations in endemic and/or pandemic situations.

Current Technology Limits

The continuous development of new anti-infective agents that act directly on the etiological target of the infection contributes more and more to the selection, mutation and resistance of pathogenic strains. This mechanism is a continuous run-up that cannot be able to prevent the emergence of new pathogenic strains that cannot be treated therapeutically. This situation pushes the pharmaceutical industry to the continuous development of new molecules which over time will again become useless in anti-infective therapy, with significant costs from a socio-economic point of view, even ethically unsustainable.
Our new patented molecules (I) are capable to block the infection in the patient without any involvement with the biology of the infective parasite (whether it is a bacterium, virus, fungus or protozoan). They considerably reduce the risks generated by the use of the commonly used anti-infective drugs. This can have a significant economic effect on reducing the estimated costs of R&D, production and therapeutic use of the anti-infective agents, with a strong reduction of the therapeutic risk and on reducing the development of new aggressive pathogens due to drug-induced selection, mutation and resistance. These results will have a powerful and positive effect on the new anti-infective therapies, with a significant impact on social and economic savings for healthcare systems worldwide.

Killer Application

These patented molecules (I) are capable, through a mechanism present in some infections (e.g. bacterial, fungal, viral and protozoal), to block the infection in the patient. On these bases they can considerably reduce the risks of selection, mutation and resistance, generated by the use of the common market known anti-infective drugs. Finally, these compounds could also be used in combination with other classes of medicaments in infections caused by pathogens of various kinds, and in the labelling of cells and tissues infected by pathogens in medical diagnostics.

Our Technology and Solution

Our patented molecules (I) are capable, through a mechanism present in some infections (e.g. bacterial, fungal, viral and protozoal), to block the infection in the patient by not attacking the infectious agent directly but by reactivating a mechanism of protection in the host cells by restoring the physiological levels of protein p53 which has a key role in the intracellular development of the pathogen.
Here we have demonstrated the ability of type (I) compounds to block in the host cells a parasitic infection of Chlamydia trachomatis. Indeed, these compounds do not exhibit any antibacterial activity when tested directly on culture of bacteria (e.g. Staphylococcus aureus). In this mechanism, during the infection, the target system is in the host cells and it has not any involvement with the biology of the infective parasite.
This model of mechanism can be translated on other pathogens that use the same physiological oncogenic mechanism in the host cells involving the modulation of the intracellular levels of p53 protein. Therefore, these Drugs, precisely because of the type of mechanism on the host, modulation of p53 levels, could simultaneously target different etiological agents including bacteria, fungi, viruses and protozoa.

Advantages

On these bases, these new compounds, not acting directly on the biology functions of the infectious agent, considerably reduces the risks of selection, mutation and resistance, generated by the use of known anti-infective drugs. The availability of new anti-infective agents capable of reducing the therapeutic risks induced by known anti-infective drugs could have a significant effect in the treatment of this type of pathologies, especially at the nosocomial level, with a reduction in treatment costs and a market advantage for the company that can develop new drugs with such a kind of mechanism.

Roadmap

Considering that at the point of development reached in the use of compounds (I) the validation of this new class of anti-infective agents is limited to the model of infection represented by Gram-negative bacteria such as Chlamydia, further investments are needed to expand the study of the activity in other types of infections. These studies can be developed on models of infections by other bacteria, viruses, fungi, and protozoa. Finally, a validation process of this type should also include the evaluation of the effects on mutation, selection and resistance of the treated pathogen strains to confirm the reduction of related risks. This type of development will also have to foresee the production on a larger scale of the molecules selected for these new studies.

Review the Technology

TRL 1

TRL 2

TRL 3

TRL 4

TRL 5

TRL 6

TRL 7

TRL 8

TRL 9

TRL

Team

Manola Comar

Director of Microbiology School at the University of Trieste and of the SC of Advanced and Translational Diagnostic Microbiology lab at IRCCS Mother Child Hospital Burlo Garofolo

Professor of Clinical Microbiology. Director of Microbiology School at the University of Trieste and of the SC of Advanced and Translational Diagnostic Microbiology lab at IRCCS Mother Child Hospital Burlo Garofolo. Head of the Italian working group of the Sexually Transmission Infection. Her main professional interests focus on women-child emerging infections, microbiology surveillance for MDR infections. She is author of more than 160 papers.

Read bio

Doretta Cuffaro

Junior Researcher at the Department of Pharmacy of the University of Pisa

She received her Ph.D. in “Drug science and bioactive substances” at the University of Pisa in 2018. The Ph.D. and the post-doc research at Prof Rossello’s group were spent on the synthesis and in vitro evaluation of metalloproteinase inhibitors. Since February 2022 she is Junior Researcher at the Department of Pharmacy of the University of Pisa, working in medicinal chemistry and nutraceutical fields.

Read bio

Lidia Ciccone

Researcher at University of Pisa

In 2011, she graduated in Medicinal Chemistry and Pharmaceutical Technology at the University of Pisa (Italy) and in 2015 she received her Ph.D. at the same University. From 2016 to 2019 she moved in France for post doctorate positions. She is researcher at University of Pisa, her research is focused on drug design guided by X-ray crystallography. Since 2015, she is author of 44 papers.

Read bio

Chiara Giacomelli

Associate professor at University of Pisa

From 2012, she has been involved in several projects focused both on the development and molecular characterization of innovative drugs, and on the investigation of molecular mechanisms of cancer progression. She has supervised several undergraduate students and co-supervised two Ph.D. students. Her research activity is attested by 58 research papers published in prestigious international journals, 11 oral communication at national and international meetings, and 5 awards

Read bio

Simona Daniele

Associate Professor in Molecular Biology at the Dept. of Pharmacy, University of Pisa

Associate Professor in Molecular Biology at the Dept. of Pharmacy, University of Pisa. Her research activity is mainly focused on intracellular pathways implicated in both neurodegenerative and cancer pathological processes. She collaborated on several projects for the development and molecular characterization of innovative combinational anticancer drugs.

Read bio

Barbara Costa

Professor of Applied Biology, Dep. of Pharmacy, University of Pisa

Professor of Applied Biology, Dep. of Pharmacy, University of Pisa. PhD in Applied Cell/Molecular Biotechnology in the Pharmacological and Biomedical sectors. Scientific research fields: i) study of the thermodynamic parameters and biological characterization of new promising therapeutic and diagnostic ligands; ii) mechanisms underlying cell functionality, differentiation and life/death balance.

Read bio

Claudia Martini

Full professor of Biochemistry, Department of Pharmacy, University of Pisa

Full professor of Biochemistry, Department of Pharmacy, University of Pisa; Advisory Board Member TLS, Toscana Life Sciences Foundation; she has won and taken part in several competitive research and technology projects; patents owner. Main research activity: Studies on the molecular mechanisms and signaling transduction systems triggered by endogenous and exogenous substances in "tube" and in cellular models.

Read bio

Elisabetta Orlandini

Associate Professor of Medicinal Chemistry to the Department of Earth Science and to the Research Centre E. Piaggio (University of Pisa)

Associate Professor of Medicinal Chemistry to the Department of Earth Science and to the Research Centre E. Piaggio (University of Pisa). Her research activity Design and synthesis of new molecules able to stabilize the proteins prone to misfolding, the protein studied is transthyretin, linked to amyloidosis, and new inhibitors of metal enzymes such as MMPs, carbonic anhydrases and HDACs useful in cancer and in neurodegenerative pathologies. She is author of 98 paper on peer-reviewed Journal and 5 patents.

Read bio

Susanna Nencetti

Associate Professor of Medicinal Chemistry at the Department of Pharmacy of the University of Pisa

Associate Professor of Medicinal Chemistry at the Department of Pharmacy of the University of Pisa. Her research activity has focused on the design and synthesis of new agents for neurodegenerative diseases and new inhibitors of metalloenzymes involved in tumor processes and complications of diabetes mellitus. She is author of 86 papers on peer-reviewed international journals and 4 patents.

Read bio

Armando Rossello

Full Professor of Medicinal Chemistry at the Department of Pharmacy, University of Pisa

Full Professor of Medicinal Chemistry at the Department of Pharmacy (DF) and affiliated to the E. Piaggio Center, University of Pisa (UniPi). He is coordinator of the ProInLab Research Laboratory at the DF, UniPi. The scientific interest is directed to the design and development of drugs and diagnostic agents that can be used in numerous degenerative pathologies and pathogen-derived infections. He is the author of over 160 publications and 16 patents.

Read bio

Elisa Nuti

Associate Professor of Medicinal Chemistry at Department of Pharmacy, University of Pisa.

Associate Professor of Medicinal Chemistry at Department of Pharmacy, University of Pisa. Her research activity is focused on the design and synthesis of new potential drug-candidates for the treatment of tumors (enzyme inhibitors targeting Matrix Metalloproteinases, ADAMs, HDACs, CAs) and inflammatory diseases. Overall, her research activity has led to 80 papers in peer-reviewed journals.

Read bio

SEE THE PATENT ON KNOWLEDGESHARE