Alzheimer’s disease (AD) is the most prevalent form of dementia, of which the pathological hallmark is brain accumulation of amyloid-β (Aβ) as well as neurofibrillary tangles of heterogenous tau proteins. Such toxic neural accumulation deadly leads to neuroinflammation, synapse failure/loss, and neurodegeneration, ultimately culminating in memory failure. Although recent advances in the understanding of neurological pathogenesis attempt to elucidate the nature of dementia and some challenging clinical trials are in progress to inactivate fatal accumulation, AD is still a disease with highly unmet medical needs due to its complex nature.
It is well known that de novo protein synthesis plays a pivotal role in synaptic plasticity and long-term memory consolidation. During the process, the elongation-competent 80S ribosome assembly at the authentic start codon is of importance to initiate protein synthesis, which is tightly regulated by intrinsic and/or extrinsic signals such as growth, injury, infection, and so on. Particularly, proper positioning of the ribosome at the initiation codon is dependent on the ternary complex (TC) comprising Met-tRNAi, GTP, and the eukaryotic initiation factor 2 (eIF2) complex. The formation of TC is regulated by its guanosine activating factor (GAF) eIF5 and its guanosine exchange factor (GEF) eIF2B complex.
Under normal conditions, TC promotes the positioning of Met-tRNAi at the start codon via GTP hydrolysis by eIF5. Inactivated TC gains activity via GDP-to-GTP conversion by eIF2B complex. However, under the stressful conditions mentioned above, several eIF2-specific kinases phosphorylate GDP-bound eIF2α subunit, which then inhibits the GEF activity of the eIF2B complex, leading to suppression of global protein synthesis to block the accumulation of aberrant misfolded proteins. Integrated stress response (ISR) attenuates global protein synthesis by inhibiting eIF2B via phosphorylation of eIF2α. A subset of mRNAs related to stress responses still actively translates to sustain restoration and recovery of cellular homeostasis.
A variety of evidence from AD patients as well as AD animal models suggests that aberrant ISR and activation of eIF2α-specific kinases are critical for the pathogenesis of AD in that (i) elevated expressions of ISR markers such as ATF4, p-PERK, ATF6, etc. are frequently observed in patients’ brains, and (ii) synthetic activation of eIF2α kinases, as well as up-regulation of p-eIF2α, is critical for promoting aberrant memory and behavioral dysfunction. A recent publication from Oliveira et al. 2021 Sci Signal clearly demonstrated that the administration of an eIF2B modulator called ISRIB confers a clinical benefit in the AD animal model.
Based on such evidence, SapiensBio starts to collaborate with ALBODARA Drug Discovery Institute (ADDI), a member of Alzheimer’s Research UK, and YD Life Science (YDLS) in 2022 to develop a first-in-class drug against AD by modulating eIF2B activity. Integration of ADDI’s valuable experience in drug development for neurological diseases, the capacity of YDLS in medicinal chemistry, and machine learning-based approach of SapiensBio in drug discovery will make a promise in securement of a successful drug candidate.