Ligands for Ser/Thr phosphoprotein phosphatases: a patent review (2005-2015)

Abstract

There is still much work to be done to validate PPP enzymes as eligible targets for the development of new drugs. The most significant barrier is likely to be persuading the majority of the scientific community that PPP enzymes are not too unspecific. Few patents disclosed the rational design of direct PPP ligands, while many inventions relied on long chain peptides-based approaches. Overall, the future of ligands for PPP enzymes as therapeutics seems both challenging and exciting.

Gramine Derivatives Targeting Ca2+ Channels and Ser/Thr Phosphatases: A New Dual Strategy for the Treatment of Neurodegenerative Diseases

“…Regarding to the τ hyperphosphorylation, the research has almost exclusively focused on the development of protein τ kinase inhibitors. We propose that the activation or the reduction of inhibitory actions over protein τ phosphatase enzymes deserves more attention, overcoming the historical prejudice of their unspecificity, currently rebutted . Of note is that when we recorded the phosphatase activity by the method of the pNPP (Table ), a substantial decrease of 70% was computed in cells exposed to the Tyr phosphatase inhibitor VO 3 – , which confirms that Tyr phosphatase activity is much more extended than Ser/Thr phosphatase activity in nervous system.…”

“…We propose that the activation, or the reduction of inhibitory actions, over protein τ phosphatase enzymes, deserves more attention, overcoming the historical prejudice of their unspecificity, currently rebutted. 32 Of note is that, when we recorded the phosphatase activity by the method of the pNPP (Table 2), a substantial decrease of 70% was 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 computed in cells exposed to the Tyr phosphatase inhibitor VO 3 -, what confirms that Tyr phosphatase activity is much more extended than Ser/Thr phosphatase activity in nervous system. The fact that τ protein is mainly dephosphorylated by PP1 and PP2A entails the advantage that Ser/Thr phosphatase activators would not present such sizeable off-target pharmacology as Tyr phosphatase activators would.…”

“…31 On the other hand, during the latest years, we have paid attention to the neurodegeneration elicited by the hyperphosphorylated τ protein and the subsequent intracellular NFT. 32 The degree of τ phosphorylation depends on the enzymatic activity of both kinases and phosphatases. 9 Tremendous scientific efforts have been invested in the development of kinase enzymes inhibitors, e.g.…”

Metal‐coordinated Hydroxide as a Nucleophile: a Brief History

“…The structurally diverse group of hydrolytic metalloenzymes includes examples utilizing both mono‐ and dinuclear central metal ions to catalyze the hydrolysis of amides and esters of carboxylic and phosphoric acids. Examples include, amongst others, the bimetallic purple acid phosphatases (PAP) (Fe III /Fe II ; Fe III /Zn II ; Fe III Mn II ),, , ureases (Ni II /Ni II ), metallo‐β‐lactamases (Zn II /Zn II ; Fe II /Fe II ), phosphotriesterases (Zn II /Zn II ; Co II /Co II ), Ser/Thr phosphatases (Fe II /Fe II ; Fe II /Zn II ; Mn II /Mn II ), and leucine aminopeptidase Zn II /Zn II ) . Mononuclear metallohydrolases containing one metal ion in the active site include carboxypeptidase and thermolysin, which both contain one Zn II ion , …”

C-glycosides analogues of the okadaic acid central fragment exert neuroprotection via restoration of PP2A-phosphatase activity: A rational design of potential drugs for Alzheimer's disease targeting tauopathies

“…Gathering all this knowledge, the early simplified view considering protein phosphatases such as PP2A, as promiscuous and unspecific enzymes without pharmacological interest, is fully overcome [17]. Nowadays, PP2A and other protein phosphatases are taken as very promising therapeutic targets for many human diseases [18]. In particular, PP2A has received vast attention in the latest years because of two main reasons.…”