Molecular mechanism of Memory
Recently, based on existing literature and basic principles of chemistry and biology, we suggest a credible model that describes the molecular basis of memory. Many neurones of all animals that exhibit memory (snails, worms, flies, vertebrae) present arborized shapes with many varicosities and boutons. These neurones, release neurotransmitters and neurometals and contain receptors (GPCRs, K channels and AchR) that are involved in read/write memory. The arborized shapes maximise neural contact with the surrounding neural Extra Cellular Matrix (nECM) as well as with other neurones through non-synaptic communication.
We propose a tripartite mechanism of non-speaking animal memory based on the dynamic interactions of neurones with the surrounding nECM+diffusibles (neurometals and neurotransmitters) called together neutrix (Figure 1). Their interactions form cognitive units of information (cuinfo) that are metal-centered complexes within the various ligands of the nECM. Emotive content is provided to memory by neurotransmitters, which embody molecular links between physiologic (body) responses and psychic feelings. We propose that neurotransmitters form mixed ternary complexes with cuinfo used for tagging emotive memory. The neurones have enormous encoding options defined by combinatorial diversity of > 10 neurometals and > 90 neurotransmitters for “flavouring” cuinfo with emotive tags. The neural network efficiently decodes and consolidates related sets of cuinfo into a coherent pattern, the basis for emotionally valued memory, critical for determining a behavioural choice aimed at survival. For more evolved animals, the neurotransmitters modulated tripartite mechanism permits of a causal connection between physiology and psychology [1-3]
Figure 1. The tripartite mechanism Figure 2. Backbone cyclization of peptides
Figure 3. Application of Cycloscan for the discovery Figure 4 Comparisons of micro-CT
of backbone cyclic drugable peptide lead images of front (left) and rear (right)
paws of CIA mice treated with PBS
(upper row), 36 pg/gr (middle row),or
360 pg/gr (bottom row) of HS(4-4)c Trp.
Figure 5. Rational conversion of the CD4 noncontinuous active region into small macrocyclic inhibitor
Development and application of technologies for the conversion of bioactive peptides and active regions in proteins into drugs.
Peptides have unfavourable pharmacokinetic and pharmacodynamic properties, such as rapid metabolism, poor bioavailability and nonselective receptor activation that prevent their development into drugs. Over the years we have developed technologies such as: Backbone Cyclization (Figure 2) and Cycloscan (Figure 3) to overcome the above mentioned disadvantages. These technologies are based on the design and synthesis of libraries of backbone cyclic peptides with conformational diversity based on a parent active peptide or active region in protein and screening them for their biological activity, metabolic stability and intestinal bioavailability. From these libraries the most active, selective, metabolically stable and orally bioavailable peptidomimetic with drug like properties is selected for in vivo preclinical studies . Following are few recent examples for the application of these technologies:
Example 1: The transmembrane helical bundle of G protein-coupled receptors (GPCRs) dimerize through helix–helix interactions in response to inflammatory stimulation. A strategy, called Helix Walk, was developed to target the helical dimerization site of GPCRs by a helix mimetic peptidomimetics with drug like properties. The Helix Walk concept was demonstrated by selecting a potent backbone cyclic helix mimetic from a library that derived from the dimerization region of chemokine (C–C motif) receptor 2 (CCR2) that is a key player in Multiple Sclerosis. We showed that CCR2 based backbone cyclic peptide having a stable helix structure inhibits specific CCR2-mediated chemotactic migration [5,6]
Example 2: We have recently proposed that a shared epitope (SE) may contribute to rheumatoid arthritis (RA) pathogenesis by acting as a ligand that activates proarthritogenic signal transduction events. We have applied the Helix Walk concept to design and prepare a backbone cyclic library based on the sequence DKCLA derived from the SE coding HLA DRBl alleles. Screening of the members of this library in vitro led to characterisation of a novel, backbone cyclic super active (IC50 1.5 picomolar) compound called HS(4-4)cTrp, containing the sequence motif DKCLA. The potently HS(4-4)c Trp, ameliorated arthritis and bone damage in vivo when administered IP in picogram doses to mice with collagen-induced arthritis (CIA) (Figure 4). The antiosteoclastogenic potency of HS(4-4)cTrp was 100,000- to 1,000,000-fold higher than the potency of a recently described linear SE 15 amino acid peptidic ligand containing the SE region [7,8].
Example 3: Rational conversion of noncontinuous active regions of proteins into a small orally bioavailable molecule is crucial for the discovery of new drugs based on inhibition of protein–protein interactions. We developed a method that utilizes backbone cyclization as an intermediate step for conversion of the CD4 noncontinuous active region into small macrocyclic molecules (Figure 5). We demonstrate that this method is feasible by preparing small inhibitor for human immunodeficiency virus infection (HIV-1). The lead compound, CG-1, inhibits growth of HIV-1 in cells and proved metabolically stable and orally available in the rat model .