Technology

History of Cannabis

It is known since ancient times that cannabis has has many therapeutic applications including its use as an analgesic, appetite enhancer, anti- inflammatory agent and in combating nausea and vomiting. However, because of its undesirable mood-altering effects, cannabis has not been fully exploited as a therapeutic agent. PafosPharma’s technology involves the creation of novel and highly effective medications that act through the endocannabinoid system without the undesirable mood-altering side effects associated with cannabis.

Scientific discoveries have shown that the human body produces endogenous cannabinoids (endocannabinoids), a family of neurotransmitters and neuromodulators. These natural substances participate in a number of physiological processes by interacting with two known cannabinoid receptors (CB1 and CB2) and are deactivated by specific enzymes and a transporter system. PafosPharma’s founder has been at the forefront of these discoveries and has contributed in a significant manner towards the characterization of the endoannabinoid therapeutic targets and the development of novel selective ligands as promising drug candidates.

Structurally dissimilar compounds are capable of interacting with CB1. The crystal structure allows us to design novel ligands with desirable specific properties and no side effects.

The CB2 crystal structure is used as a template for the design and synthesis of improved drugs.

The Endocannabinoid System (ECS)

Cannabinergic drugs modulate the central nervous and immune systems by acting through two receptors (CB1 and CB2) and two classes of endogenous ligands represented by anandamide and 2-arachidonoyl glycerol (endocannabinoids). The ECS serves a vital purpose for our health and well-being because it regulates key aspects of our biology. The Center for Drug Discovery (CDD) a closely collaborating research laboratory studies the interactions of cannabinergic ligands with the above receptors, enzymes and transporters using a combination of chemical, biochemical, biophysical, and computational methods. These drug targets include the known cannabinoid receptors (CB1 and CB2) as well as key enzymes involved in modulating the system including fatty acid amide hydrolase (FAAH), monoacylglyceral lipase (MGL), N-acylethanolamine-hydrolyzing amidase (NAAA); diacylglycerol lipase (DGL), ABHD6 as well as the cannabinoid transporter system. Our results are then used to design and synthesize novel, patented therapeutically useful drugs.
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Activating the Body's Natural Neuroprotection System

PafosPharma’s research focuses on activating the ECS neruroprotective system of the body. This is produced by modulating the functions of key endocannabinoid proteins including the CB1 and CB2 receptors as well as those that manage the levels of endocannabinoids.

Research Capabilities

PafosPharma’s research approach reduces drug development risk by designing small-molecule drug candidates that optimize desired properties of cannabinoids, while reducing these side effects. This involves the design and synthesis of the cannabinergic target. The improved drugs avoid off-target side effects and possess improved absorption/degradation profiles to limit dependency and abuse potential. Pafos’s research uses highly predicitive animal models to evaluate safety and efficacy early in the process.

The Company has strong medicinal chemistry assisted by molecular modeling (proprietary receptor and enzyme models). Pafos has (in conjunction with the Center for Drug Discovery, (CDD) Northeastern University). Biophysical facilities for drug design (including extensive NMR and computational capabilities), enzymes and receptors cloned and purified from bacterial and mammalian expression systems, HTS fluorescent assays using expressed and purified drug targets, and measurement of bioavailability and PK using LC/MS/MS Animal models of inflammatory conditions.

Rational Design Optimizes Safety and Efficacy

Our drug design is assisted by the use of ligand-assisted Protein Structure (LAPS) is a cellular-molecular biology/proteomic experimental paradigm for mapping and targeting putatively critical amino acid residues in the ligand-binding domains of functional proteins. LAPS integrates multiple techiques:

Express human recombinant endocannabinoid-system protein (enzymes, receptor) in bioactive form (catalytically active, binding and signaling component).
Isolate and purify the active protein
Determine protein primary structure using mass spectrometry (MS)-based proteomics
Digest protein
Determine amino acid sequence and mass of each digest peptide
Identify or design covalent probes as ligands with chemically reactive groups selective for specific amino acids within the protein target
Use mass spectrometry-based proteomics to identify protein-ligand interaction sites(s) under physiological conditions (pH)
Mutate amino acid(s) at putative interaction sites and re-examine protein activity/ligand interaction profile with mutant enzyme/receptor.

Pafos’s approach allows us to manage the time during which the drug is active, avoid any issues related to tolerance and reduce no undesirable drug metabolites.