For scientific and clinical purposes, pain is defined by the International Association for the Study of Pain (IASP) as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage". Pain, in general, may be divided into two subtypes: acute and chronic. Acute pain has a relatively short duration and a sudden onset. One type of acute pain, for example, is cutaneous pain felt on injury to the skin or other damaged tissues. Cutaneous nociceptors (pain-sensitive nerve endings) terminate just below the skin, and due to the high concentration of nerve endings, produce a well defined, localized pain of short duration. Chronic pain refers to a pain that persists after an acute injury, pain related to a persistent or degenerative disease and long-term pain from an unidentifiable cause, such as fibromyalgia. Common types for chronic pain include neuropathic pain, caused by damage to the nervous system such as diabetic neuropathies, inflammatory pain associated with arthritis and rheumatoid diseases, low back pain, cancer pain, post-operative pain and visceral pain. BLV200704 is a small molecule that acts on the central nervous system as a potent analgesic. It is a derivative of an endogenous analgesic molecule, which has been chemically modified in order to achieve the excellent drug-like properties that make of BLV200704 a strong candidate for treatment of both acute and chronic pain.
The heme-containing enzyme 2,3 indoleamine dioxygenase (IDO) catalyzes the first and rate-limiting step in the oxidative degradation of tryptophan through the kynurerenine pathway. IDO is widely expressed in human tissues and cell subsets and is induced during inflammation by IFN- and other inflammatory cytokines. Several studies have demonstrated a crucial role for IDO in the induction of immune tolerance during infection, pregnancy, transplantation, autoimmunity, cancer and neurological disorders. The IDO Programme is derived from the BLOCKADE application of GPSD2, a potent yeast screening system that is able to identify high quality hit molecules with the capacity to inhibit human IDO. The set of Hit molecules selected by the BLOCKADE screening application entered the IDO Programme and is currently being developed into very efficacious drug-like compounds to be used as medicines for the different medical conditions mediated by the up-regulation of IDO.
Tau aggregation into neuroflibrillary tangles (NFT) is one of the major features in Alzheimer's disease and in several other dementias and movement disorders, including Corticobasal Degeneration (CBD), Frontotemporal Dementia with Parkinsonism linked to Chromosome 17 (FTDP17), Pick's Disease (PiD) and Progressive Supranuclear Palsy (PSP). This group of diseases is commonly referred to as tauopathies. Tau protein interacts with tubulin to stabilize microtubules and promote tubulin assembly into microtubules. The NFTs observed in tauopathies are enriched in abnormally hyperphosphorylated tau, which is less competent in binding to and stabilizing microtubules. As a result of altered protein tau, a variety of deleterious cellular processes is triggered, such as a destabilised microtubule network, impaired axonal transport, formation of NFTs and neuronal cell death. The DISAGGREGATOR-TAU application of GPSD2 was generated with the goal of identifying compounds that can act as modulators of the cellular toxicity induced by altered protein tau. Hit molecules selected by high-throughput screening with this application are being developed into compounds with therapeutic action in disorders mediated by protein tau. The TAU Programme aims at generating drug-like molecules with optimal properties in terms of safety and efficacy for the treatment of tau-related diseases, with a particular focus on Alzheimer’s Disease due to the dramatic clinical relevance and social burden of this particular pathology.
Familial amyloid polyneuropathy (FAP) is a neurodegenerative disease characterized by the systemic deposition of amyloidogenic variants of the transthyretin (TTR) protein, particularly in the peripheral nervous system. The most common mutation causing FAP is TTR V30M. In addition to causing FAP, TTR mutations are also associated with senile systemic amyloidosis (SSA), and familial amyloid cardiomyopathy (FAC). TTR is a homotetramer formed by a dimer of dimers. Mutations in the TTR monomer decrease the stability of the tetramer, leading to dissociation and subsequent amyloid deposition. The DISAGGREGATOR-TTR application of GPSD2 was generated with the goal of identifying molecules with the potential to ameliorate the effect of the mutations in the TTR protein. Hit molecules derived from the HTS campaign will be developed into drug-like molecules for the treatment of FAP.
Cystic fibrosis (CF) is a hereditary disease caused by mutations in a membrane-bound chloride channel, named Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). The disease is associated to a strong reduction/absence of chloride ion transport across the apical membrane of the epithelium, resulting in poorly hydrated, thickened mucous secretions in the lungs. The most common mutation is ΔF508, accounting for two-thirds of CF cases worldwide. As a result of the ΔF508 mutation, the CFTR protein does not fold normally, fails to escape the endoplasmic reticulum and is rapidly degraded. It is estimated that a very small improvement in the biosynthetic maturation of mutant CFTR, boosting CFTR functional activity from less than 1% to as little as 5% of normal levels, would be sufficient to reduce disease severity or even eliminate the principal disease manifestations. Therefore, the identification of molecules that could act as "correctors" of mutated CFTR protein is a field of research with enormous therapeutic potential. BIOALVO developed the DISAGGREGATOR-CFTR application of GPSD2 as a screening tool for the identification of compounds with the potential to ameliorate the effect of the mutations in the CFTR protein. Hit molecules derived from the HTS campaign will be developed into drug-like molecules for the treatment of CF.
The pathological hallmarks of Alzheimer's Disease are plaques of A peptide and tangles of hyperphosphorylated tau. To what extent A and tau abnormalities are linked and whether either represents an upstream pathogenic cause driving the disease has been a matter of extensive debate. In order to account for the synergistic interaction between A and tau dysfunction, BIOALVO developed the TAU/Aβ application of GPSD2. Hit molecules derived from the screening of this platform are potential therapeutic modulators of altered cellular mechanisms underlying the pathogenesis of Alzheimer's Disease.