8
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      A phase 1 study to evaluate the safety and pharmacokinetics of PQ912, a glutaminyl cyclase inhibitor, in healthy subjects

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Introduction

          Pyroglutamate-amyloid-β (pE-Aβ) peptides are major components of Aβ-oligomers and Aβ-plaques, which are regarded as key culprits of Alzheimer's disease (AD) pathology. PQ912 is a competitive inhibitor of the enzyme glutaminyl cyclase (QC), essential for the formation of pE-Aβ peptides.

          Methods

          A randomized, double-blind, placebo-controlled, single- and multiple-ascending oral dose study investigated the safety, pharmacokinetics, and pharmacodynamics of PQ912 in healthy nonelderly and elderly subjects.

          Results

          PQ912 was considered safe and well tolerated with dose-proportional pharmacokinetics up to doses of 200 mg. At higher doses up to 1800 mg, exposure was supraproportional and exposure in elderly subjects was approximately 1.5- to 2.1-fold higher. Exposure in cerebrospinal fluid (CSF) was approximately 20% of the unbound drug in plasma, and both serum and CSF QC activity was inhibited in a dose-related manner.

          Discussion

          This first-in-man study of a compound-targeting QC inhibition justifies further development of PQ912 for the treatment of AD.

          Related collections

          Most cited references24

          • Record: found
          • Abstract: found
          • Article: not found

          Prion-Like Behavior and Tau-dependent Cytotoxicity of Pyroglutamylated β-Amyloid

          Extracellular plaques of β-amyloid (Aβ) and intraneuronal neurofibrillary tangles made from tau are the histopathological signatures of Alzheimer’s disease (AD). Plaques comprise Aβ fibrils that assemble from monomeric and oligomeric intermediates, and are prognostic indicators of AD. Despite the significance of plaques to AD, oligomers are considered to be the principal toxic forms of Aβ 1,2 . Interestingly, many adverse responses to Aβ, such as cytotoxicity 3 , microtubule loss 4 , impaired memory and learning 5 , and neuritic degeneration 6 , are greatly amplified by tau expression. N-terminally truncated, pyroglutamylated (pE) forms of Aβ 7,8 are strongly associated with AD, are more toxic than Aβ1–42 and Aβ1–40, and have been proposed as initiators of AD pathogenesis 9,10 . We now report a mechanism by which pE-Aβ may trigger AD. Aβ3(pE)-42 co-oligomerizes with excess Aβ1–42 to form metastable low-n oligomers (LNOs) that are structurally distinct and far more cytotoxic to cultured neurons than comparable LNOs made from Aβ1–42 alone. Tau is required for cytotoxicity, and LNOs comprising 5% Aβ3(pE)-42 plus 95% Aβ1–42 (5% pE-Aβ) seed new cytotoxic LNOs through multiple serial dilutions into Aβ1–42 monomers in the absence of additional Aβ3(pE)-42. LNOs isolated from human AD brain contained Aβ3(pE)-42, and enhanced Aβ3(pE)-42 formation in mice triggered neuron loss and gliosis at 3 months, but not in a tau null background. We conclude that Aβ3(pE)-42 confers tau-dependent neuronal death and causes template-induced misfolding of Aβ1–42 into structurally distinct LNOs that propagate by a prion-like mechanism. Our results raise the possibility that Aβ3(pE)-42 acts similarly at a primary step in AD pathogenesis.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Amyloid beta protein (A beta) deposition: A beta 42(43) precedes A beta 40 in Down syndrome.

            The chronological relationship regarding deposition of amyloid beta protein (A beta) species, A beta 40 and A beta 42(43), was investigated in 16 brains from Down syndrome patients aged 31 to 64 years. The frontal cortex was probed with two end-specific monoclonals that recognize A beta 40 or A beta 42(43). All senile plaques detected with an authentic beta monoclonal were also A beta 42(43) positive, but only a varying proportion was A beta 40 positive. In young ( 50 years old) brains contained many mature senile plaques with amyloid cores in addition to diffuse and immature plaques and the proportion of A beta 40-positive senile plaques was increased (mean, 42% of total). Cerebral amyloid angiopathy was more abundant in old Down syndrome brains and was positive for both A beta 40 and A beta 42(43). In cerebral amyloid angiopathy, A beta 40 predominated over A beta 42(43) in both staining intensity and number of positive vessels. These results indicate that (1) the A beta species initially deposited in the brain as senile plaques is A beta 42(43) and A beta 40 only appears a decade later, and (2) in cerebral amyloid angiopathy A beta 40 appears as early as A beta 42(43).
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Glutaminyl cyclases unfold glutamyl cyclase activity under mild acid conditions.

              N-terminal pyroglutamate (pGlu) formation from glutaminyl precursors is a posttranslational event in the processing of bioactive neuropeptides such as thyrotropin-releasing hormone and neurotensin during their maturation in the secretory pathway. The reaction is facilitated by glutaminyl cyclase (QC), an enzyme highly abundant in mammalian brain. Here, we describe for the first time that human and papaya QC also catalyze N-terminal glutamate cyclization. Surprisingly, the enzymatic Glu(1) conversion is favored at pH 6.0 while Gln(1) conversion occurs with an optimum at pH 8.0. This unexpected finding might be of importance for deciphering the events leading to deposition of highly toxic pyroglutamyl peptides in amyloidotic diseases.
                Bookmark

                Author and article information

                Contributors
                Journal
                Alzheimers Dement (N Y)
                Alzheimers Dement (N Y)
                Alzheimer's & Dementia : Translational Research & Clinical Interventions
                Elsevier
                2352-8737
                03 October 2015
                November 2015
                03 October 2015
                : 1
                : 3
                : 182-195
                Affiliations
                [a ]Probiodrug AG, Halle (Saale), Germany
                [b ]Covance Clinical Research Unit AG, Allschwil (Basel), Switzerland
                [c ]Covance Clinical Research Unit Ltd, Leeds, UK
                Author notes
                []Corresponding author. Tel.: +49-174-1962817; Fax: +49-151-23579860. Inge.Lues@ 123456probiodrug.de
                [1]

                Present address: Serumwerk Bernburg AG, D-06406 Bernburg, Germany.

                [2]

                Present address: St. Annaweg 28, CH-4112 Flüh, Switzerland.

                [3]

                Present address: Covance Ltd, Osprey House, Westacott Way, Maidenhead, SL6 3QH, UK.

                Article
                S2352-8737(15)00022-0
                10.1016/j.trci.2015.08.002
                5975062
                29854937
                52a45b3b-2fda-400d-b929-d54e19b46d6a
                © 2015 Probiodrug AG, Germany

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Categories
                Featured Article

                alzheimer's disease,glutaminyl cyclase,qc inhibitor,amyloid-beta,pyroglutamate,pe-aβ,cerebrospinal fluid

                Comments

                Comment on this article