The “promiscuous drug concept” with applications to Alzheimer's disease

Abstract

Arguably, Alzheimer's disease (AD) is a multifactorial syndrome, rather than single disease, arising from a complex array of neurochemical factors. Numerous studies on the molecular pathogenesis of AD implicate a diversity of factors ranging from neurotoxic peptides (b-amyloid) to inflammatory processes (interleukins), but all culminating in a common neuropathology. This diversity of molecular causation is an impediment to the design of effective therapies for AD. To address this design problem, we sought to identify a single, common motif (a ''common receptor'') shared by multiple structurally and functionally diverse proteins implicated in AD. This search revealed the presence of a common BBXB peptide motif and upon refinement, an AXBBXB motif; these regions can be exploited for the design of a ''promiscuous drug'' that exploits a ''one-drug-multiplereceptors'' therapeutic strategy for AD.

Modeling Promiscuity Based on in vitro Safety Pharmacology Profiling Data

“…There are a few exceptional cases for which the design of compounds with multiple activities in a given pathway may be desirable. These include some well-known examples in depression, schizophrenia, [1] and Alzheimer's disease, [2] but also in oncology, [3] showing that a weaker selectivity is key to the efficacy of a significant number of approved drugs. However, promiscuity in these cases is often limited to a particular subclass of targets (for example, kinases).…”

Searching for an endogenous anti-Alzheimer molecule: identifying small molecules in the brain that slow Alzheimer disease progression by inhibition of β-amyloid aggregation

“…This BBXB motif, where "B" is any of the amino acids with basic properties and X is any amino acid, has been identified as one that appears in many of the proteins affiliated with Alzheimer disease. 13 Assuming an α-helical conformation and using a molecular mechanics energy minimized geometry of HHQK, the 1-2, 1-4 and 2-4 inter-residue side-chain charge separations are 7.1 Å, 8.5 Å and 13.2 Å, respectively. To establish energetically favourable intermolecular interactions with these cationic basic B-type residues, a preferred method is via an anionic group (forming a cationic-anionic interaction).…”

“…2 The proposed causative agent in Alzheimer disease is the β-amyloid protein, ranging in length from 39 to 43 amino acids. 3,4 A small, 4-residue segment within β-amyloid, histidine 13 -histidine-glutamine-lysine 16 (HHQK; Appendix 1, Fig. S1, available at cma.ca/jpn), has been identified as a region that plays a mechanistic role in the conversion of β-amyloid from a nontoxic α-helical or random coil con formation to the β-sheet conformation that leads to aggregation and neurotoxicity.…”

Oligonucleotide Delivery with Cell Surface Binding and Cell Penetrating Peptide Amphiphile Nanospheres

“…This sequence was found to be consensus in heparin binding peptides and proteins 15 and has been proposed as a potential common-receptor binding peptide for drug delivery. 19 In addition to the proteoglycan binding propensity of KRSR peptide, its basic nature also fortifies the binding to the cell surface membrane and enables translocation of the cargo similarly to other cell-penetrating peptides. K-PA was used as a nonbioactive PA control.…”