Teriparatide biosimilar(Rhein-Minapharm)

Parathyroid hormone (PTH) agonists and antagonists have been shown to improve hair growth after chemotherapy; however, rapid clearance and systemic side‐effects complicate their usage. To facilitate delivery and retention to skin, we fused PTH agonists and antagonists to the collagen binding domain (CBD) of Clostridium histolyticum collagenase. in‐vitro studies showed that the agonist fusion protein, PTH‐CBD, bound collagen and activated the PTH/parathyroid hormone‐related peptide receptor in SaOS‐2 cells. The antagonist fusion proteins, PTH(7–33)‐CBD and PTH([‐1]‐33)‐CBD, also bound collagen and antagonized PTH(1–34) effect in SaOS‐2 cells; however, PTH(7–33)‐CBD had lower intrinsic activity. Distribution studies confirmed uptake of PTH‐CBD to the skin at 1 and 12 hr after subcutaneous injection. We assessed in vivo efficacy of PTH‐CBD and PTH(7–33)‐CBD in C57BL/6J mice. Animals were depilated to synchronize the hair follicles; treated on Day 7 with agonist, antagonist, or vehicle; treated on Day 9 with cyclophosphamide (150 mg/kg i.p.) or vehicle; and sacrificed on Day 39. Normal mice (no chemo and no treatment) showed rapid regrowth of hair and normal histology. Chemo + Vehicle mice showed reduced hair regrowth and decreased pigmentation; histology revealed reduced number and dystrophic anagen/catagen follicles. Chemo + Antagonist mice were grossly and histologically indistinguishable from Chemo + Vehicle mice. Chemo + Agonist mice showed more rapid regrowth and repigmentation of hair; histologically, there was a normal number of hair follicles, most of which were in the anagen phase. Overall, the agonist PTH‐CBD had prominent effects in reducing chemotherapy‐induced damage of hair follicles and may show promise as a therapy for chemotherapy‐induced alopecia.

The N‐terminal 1–34 fragment of parathyroid hormone (PTH) is fully active in vitro and in vivo and reproduces all biological responses characteristic of the native intact PTH. In order to develop safer and non‐parenteral PTH‐like bone anabolic agents, we have studied the effect of introducing conformationally constrained dipeptide mimetics into the N‐terminal portion of PTH in an effort to generate miniaturized PTH‐mimetics. To this end, we have synthesized and conformationally and biologically characterized PTH(1–11) analogues containing 3R‐carboxy‐6S‐amino‐7,5‐bicyclic thiazolidinlactam (7,5‐bTL), a rigidified dipeptide mimetic unit. The wild type sequence of PTH(1–11) is H‐Ser‐Val‐Ser‐Glu‐Ile‐Gln‐Leu‐Met‐His‐Asn‐Leu‐NH2. The following pseudo‐undecapeptides were prepared: [Ala1, 7,5‐bTL3, 4, Nle8, Arg11]hPTH(1–11)NH2 (I); [Ala1, 7,5‐bTL6, 7, Nle8, Arg11]hPTH(1–11)NH2 (II); [Ala1, Nle8, 7,5‐bTL9, 10, Arg11]hPTH(1–11)NH2 (III). In aqueous solution containing 20% TFE, only analogue I exhibited the typical CD pattern of the α‐helical conformation. NMR experiments and molecular dynamics calculations located the α‐helical stretch in the sequence Ile5‐His9. The dipeptide mimetic unit 7,5‐bTL induces a type III β‐turn, occupying the positions i − 1 and i of the turn. Analogue II exhibited an equilibrium between a type I β‐turn and an α‐helix, and analogue III did not show any ordered structure. Biological tests revealed poor activity for all analogues (EC50 > 0.1 mM). Apparently, the relative side‐chain orientation of Val2, Ile5 and Met8 can be critical for effective analogue‐receptor interaction. Considering helicity as an essential property to obtain active PTH agonists, one must decorate the correctly positioned dipeptide mimetic azabicycloalkane scaffold with substitutions corresponding to the displaced amino acids. Copyright © 2007 European Peptide Society and John Wiley & Sons, Ltd.