From Combinations to Single-Molecule Polypharmacology—Cromolyn-Ibuprofen Conjugates for Alzheimer’s Disease

Abstract

Despite Alzheimer’s disease (AD) incidence being projected to increase worldwide, the drugs currently on the market can only mitigate symptoms. Considering the failures of the classical paradigm “one target-one drug-one disease” in delivering effective medications for AD, polypharmacology appears to be a most viable therapeutic strategy. Polypharmacology can involve combinations of multiple drugs and/or single chemical entities modulating multiple targets. Taking inspiration from an ongoing clinical trial, this work aims to convert a promising cromolyn–ibuprofen drug combination into single-molecule “codrugs.” Such codrugs should be able to similarly modulate neuroinflammatory and amyloid pathways, while showing peculiar pros and cons. By exploiting a linking strategy, we designed and synthesized a small set of cromolyn–ibuprofen conjugates (4–6). Preliminary plasma stability and neurotoxicity assays allowed us to select diamide 5 and ethanolamide 6 as promising compounds for further studies. We investigated their immunomodulatory profile in immortalized microglia cells, in vitro anti-aggregating activity towards Aβ42-amyloid self-aggregation, and their cellular neuroprotective effect against Aβ42-induced neurotoxicity. The fact that 6 effectively reduced Aβ-induced neuronal death, prompted its investigation into an in vivo model. Notably, 6 was demonstrated to significantly increase the longevity of Aβ42-expressing Drosophila and to improve fly locomotor performance.

Discovery of Dual Aβ/Tau Inhibitors and Evaluation of Their Therapeutic Effect on a Drosophila Model of Alzheimer’s Disease

“…45 Doxycycline was tested at 50 μM, a concentration used in similar previous experiments. 59 As shown in Figure 5A, after 20 days, only 50% of Aβ 42 flies were still alive. Importantly, treatment with both 22 and 23 resulted in an increase in longevity, being comparable to that of the reference compound doxycycline (at a higher concentration).…”

“…We again used as control the antibiotic doxycycline, which is capable of halting amyloid aggregation of several disease-associated proteins (including Aβ and Tau) . Doxycycline was tested at 50 μM, a concentration used in similar previous experiments . As shown in Figure A, after 20 days, only 50% of Aβ 42 flies were still alive.…”

“…Climbing Assay and the Survival Rate. The behavioral assays follow the protocol illustrated in Albertini et al 59 Briefly, males and females 25 per vial were kept at 25 °C. The climbing test was performed on days 7, 14, and 21 after birth.…”

Impact of New Drugs for Therapeutic Intervention in Alzheimer’s Disease

“…After many failures with monotreatments, the combination of cromolyn and ibuprofen (ALZT-OP1) has been proposed as a suitable treatment for LOAD [28]. Cromolyn acts as a modulator of MCs and microglia, as well as an Aβ oligomerization inhibitor [104]. In turn, ibuprofen is an anti-inflammatory drug with interesting effects such as αsecretase activation -thus modulating Aβ production-, microglia inhibition, activation of PPAR γ and modulation of synapses through the inhibition of Rho family GTPases [105][106][107].…”

Exploring EZH2-Proteasome Dual-Targeting Drug Discovery through a Computational Strategy to Fight Multiple Myeloma

“…As a drawback, due to their high degree of centrality, the targeting of either of these two proteins is also prone to off-target effects in normal tissue; however, these are relatively less likely seeing as EZH2 and P20S have comparatively high local-to-global importance ratio (i.e., are placed at 50% of the ranking of degree-to-betweenness ratio). Nonetheless, dual-targeting therapy is in itself an important strategy to offset possible side effects as they allow lowering the therapeutic dose [24][25][26] and have been associated with a better toxicity-efficacy balance [27]. P20S has already been the focus of different dual-targeting strategies for drug development whereby compounds were developed to directly modulate P20S and, simultaneously, HDAC6 [28], HDAC1 [29], and fatty acid synthase [30], among others.…”