Research
Our research activities emphasize the integration of combinatorial chemistry, microwave-assisted organic synthesis (MAOS), multicomponent reactions (MCR), electrochemistry and computational techniques to speed-up the drug-discovery process by rational exploration of the biologically relevant chemical space.
Different approaches are used in our lab to discover new drug candidates: 1) Diversity oriented synthesis (DOS) from privileged scaffolds; 2) Target-based drug discovery (TBDD); 3) Phenotypic drug discovery (PDD); 4) Mechanistic-informed PDD (MIPDD); 5) Prebiotic chemistry.
Antiviral Drug Discovery
Five decades after the description of the first antiviral drug, viral pathogens, including “old” re-emerging viruses and “new” emerging viruses still represent a serious threat for global health due to enhanced globalization and climate changes.
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Our approach:
- Multitarget antivirals (may retain activity in case of viral mutations; may have a better compliance; may be cheaper than a combination treatment).
- Host-targeting antivirals (may inhibit different viruses which depends on the same host factor; may act as pennicilin-like/broad-spetrum antivirals).
Particular attention is paid to neglected diseases caused by Dengue/Zika virus, Enterovirus/Rhinovirus and releted co-infections.
Cystic Fibrosis Drug Discovery
Cystic fibrosis is a complex disease which arises from the mutation of a gene, located on the long arm of chromosome 7 and encoding for cystic fibrosis transmembrane conductance regulator (CFTR), but involves many aspects such as inflammation and infections. At pulmonary level, CFTR mutations trigger a spiral of negative events leading to pulmonary exacerbation.
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Challenges:
- Requires a complex therapeutic regimen with multiple drugs (therapeutic burden)
- Virus-bacteria co-infections
- Drugs that specifically target CF inflammation remain elusive
Our approach:
- Multitarget agents to treat co-infections
- Modulators of the CCR6/CCL20 axis as specific anti-inflammatory approach
Discovery of new PCSK9 inhibitors
Hypercholesterolemia is one of the main risk factors for the onset of cardiovascular diseases (CVDs), which represent the leading cause of death worldwide. Statins are the first-line therapy for hypercholesterolemia treatment, are highly effective but affected by important limitations. PCSK9 emerged in the last few years as a new promising target for the reduction of circulating cholesterol but orally available anti-PCSK9 small-molecule drugs are still missing.
Inflammatory Bowl Disease (IBD)
Inflammatory bowel diseases (IBD), comprising Crohn’s disease (CD) and ulcerative colitis (UC), represents a complex of chronic relapsing inflammatory disorders of the intestine whose impact on everyday life is dramatic. In the western world IBD incidence is steadily increasing (up to 0.5% of the general population), representing a huge economic burden for the society in terms of direct and indirect costs. Although etiology is still poorly defined, a central role is played by the continuous recruitment of leukocytes from the circulation to inflamed tissues.
Prebiotic Chemistry
At the origin, Multi Component Chemistry (MCC) produced incredible high chemical diversity on our Planet (heterocycles, carbohydrates, nucleic acids etc.), which spontaneously assembled in a highly organized system under evolutionary pressure till the emergence of the Last Universal Common Ancestor (LUCA). It is known that ancestral viruses have co-evolved with the Last Universal Common Ancestor (LUCA) by sharing and exploiting the same chemical toolset.
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Challenges:
- Requires a complex therapeutic regimen with multiple drugs (therapeutic burden)
- Virus-bacteria co-infections
- Drugs that specifically target CF inflammation remain elusive
Challenges:
- Requires a complex therapeutic regimen with multiple drugs (therapeutic burden)
- Virus-bacteria co-infections
- Drugs that specifically target CF inflammation remain elusive
CNS Drug Discovery
Parkinson's disease (PD) is recognized as a second common inflammatory neurodegenerative disorder after AD. It is characterized by the accumulation of aggregated proteins within neuronal cell bodies and microglia, which is associated with microglial activation and neuronal death. Several biological targets are being exploited for therapeutic intervation but, today, the treatment is symptomatical rather than preventive or curative and this leaves the field open for the search of novel drug candidates and pharmacological appraoches.
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Challenges:
- LRRK2 kinase inhibitors targeting the conserved catalytic pocket may have on-target and off-target side effects.
- Familial and idiopathic PD patients showed high iron level in the substantia nigra (SN) pars compacta.
- Aggregates within neurons induce the production of pro-inflammatory cytokines/chemokines and T cells infiltration (especially Th17) that ultimately leads to neuronal death.
Challenges:
- LRRK2 kinase inhibitors targeting the conserved catalytic pocket may have on-target and off-target side effects.
- Familial and idiopathic PD patients showed high iron level in the substantia nigra (SN) pars compacta.
- Aggregates within neurons induce the production of pro-inflammatory cytokines/chemokines and T cells infiltration (especially Th17) that ultimately leads to neuronal death.
Anticancer Drug Discovery
One of the main drawbacks of conventional chemotherapy is that drugs kill both cancer and healthy cells indiscriminately. Targeted cancer therapy has been a valuable breakthrough in focusing treatment directly on cancer cells while sparing healthy ones. Despite several new anticacer drugs have reached the market, cancer metastases represent the leading reason for treatment failure and mortality.
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Challenges:
- On-target resistant mechanism of kinases involved in cancer progression.
- Cancer metastasis.
Our approach:
- Allosteric kinase inhibitors.
- GPCR targeting.
Particular attention is paid to leukemia, breast cancer and neuroblastoma
.....to boldly go where no medicinal chemist has gone before
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