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  • Primarily because secretase was a therapeutic target

    2022-08-12

    Primarily because γ-secretase was a therapeutic target in AD, a plethora of γ-secretase inhibitors (GSIs) have been developed that effectively inhibit γ-secretase cleavage in humans [16]. Indeed, “druggability” of γ-secretase has not been an issue even when the identity of the target was unknown in these blind screens. γ-Secretase is a highly tractable therapeutic target and numerous orally-bioavailable, Cy5 amine (non-sulfonated) penetrant GSIs have been developed [16], [17] (see Fig. 2 for examples). Many of these GSIs are highly potent and show excellent bioavailability and pharmacokinetic properties. In AD the efficacy of GSIs has been tied to inhibition of amyloid β protein (Aβ); thus, in AD, GSIs have been conceptualized as “Aβ production inhibitors” [16]. GSIs can decrease Aβ production in human and mouse brain and chronic administration decreases Aβ deposition in amyloid β protein precursor (APP) mouse models [18], [19], [20], [21]. These GSIs have been important tools in the AD field, but also have served as essential elements of preclinical proof of concept studies for many different disease indications. In addition to GSIs, compounds referred to as γ-secretase modulators (GSMs) that modulate processivity of γ-secretase have been identified and remain in development as potentially inherently safe ways to selectively target Aβ42 in AD.
    GSIs In the mid to late 1990s, cell-based drug screens conducted by multiple groups searching for inhibitors of Aβ production identified a number of compounds that dramatically inhibited Aβ secretion and increased levels of APP carboxyl terminal fragments (CTFs) produced by prior α- or β-secretase catalyzed ectodomain shedding [22], [23], [24], [25], [26], [27], [28], [29]. At the time the first compounds with these effects on APP processing were identified, the protease targeted was unknown, but the cleavage activity was referred to as γ-secretase. Thus, compounds with this profile were named GSIs. Because γ-secretase cleaved APP within its transmembrane domain and generated multiple Aβ peptides, there were many hypotheses regarding the nature of the activity and the proteases responsible [30], [31]. Furthermore, at that time, there was general resistance to the concept that a protease could cleave peptide bonds normally present within the transmembrane domain (TMD) of a protein, fueling further speculation regarding the nature of the protease responsible. Several inhibitor studies also demonstrated that γ-secretase possessed multiple pharmacologically dissociable cleavage activities indicating that it may be more than one protease [32], [33]. However, genetic, GSI binding, biochemical and mutational analyses soon demonstrated that γ-secretase was a multi-protein complex with the PSEN1 or PSEN2 acting as the catalytic core, and three accessory proteins, APH1, PEN2, and Nicastrin, needed for complex assembly and stability in cells [1], [2], [3], [34]. Although it remains formally possible that small-molecules that inhibit γ-secretase cleavage could bind one of the other subunits, GSI binding studies suggest that the target of most GSIs is PSEN1 and 2. PSEN1 and 2 are now known to be part of a larger family of intramembrane cleaving aspartyl proteases which include five human homologs referred to as signal peptide peptidases (SPP (HM123), SPPL3, SPPL2a,b,c) [35], [36], [37]. SPPs differ from PSENs in that they cleave the transmembrane domain of type 2 as opposed to type 1 membrane proteins, and at least for SPP (HM13), the apparent lack of requirement for co-factors for activity [35], [38], [39]. The differential cleavage specificity appears to be determined by the opposite orientation of the two catalytic aspartate residues between SPPs and PSEN family members. Of note, the recent crystal structure of an SPP from archaeon Methanoculleus marisnigri JR1 was established [40]. This structure showed that the catalytic aspartates residues that reside within opposing transmembrane domains are in close proximity to each other and the lipid membrane surface.