Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • Extending time action is another

    2021-09-23

    Extending time action is another strategy to increase in vivo efficacy. Twice daily administration of the unacylated analogs herein caused greater body weight loss in DIO mice than the equivalent dose administered as a single daily injection, suggesting that protracted time action should yield more effective therapy. As such, we report a fatty acylated, Aib2 substituted analog of hGIP lowered body weight in DIO mice following chronic administration. However, the pharmacokinetic profile for this analog was not studied but is expected to be similar to comparably acylated peptides such as liraglutide. This effect size on body weight is consistent with that achieved with chronic BID administration of another equivalent acylated analog, although statistical significance was not reached in that study [21]. However, another long-acting GIP analog, presumably lipidated with a diacid-based fatty Oxybutynin sale although the structure was not reported, failed to significantly lower body weight in DIO mice at high doses; however, potency at mGIPR was not reported for that analog either [8]. Native, full-length GIP has limited aqueous solubility and is prone to aggregation in liquid formulations. Since the C-terminal tail of GIP is dispensable for activity at the receptor [38], we chose to explore more radical modifications to this region. The C-terminal tail of native GIP can be replaced with the C-terminal extension of exendin-4 (Cex) to improve biophysical properties and physiological stability, and notably has been utilized in other GIPR agonists [5], [25]. Our Cex-substituted analogs proved similarly efficacious on body weight as GIP analogs with a native C-terminal tail, however C-terminally truncated molecules were not studied for effects on body weight. Recent commercialization attempts have focused on attenuating GIP action for metabolic benefits. An intellectual property filing (WO2017/112824) shows that treatment with an anti-GIPR antibody alone slows body weight gain in growing DIO mice and obese monkeys, and potentiates the body weight benefits of GLP-1R agonists. Sufficient peer review is required to verify the results, particularly the selectivity profile towards GIPR since antibodies directed to G protein-coupled receptors can be promiscuous. It has been speculated, albeit not rigorously tested, that the acute effects of GIP on adipose tissue vasoactivity and fatty acid re-esterification in humans would eventually progress to increased adiposity with continuous exposure [39]. However, it is important to note that the contributing effects of insulin cannot be excluded, and GLP-1 has also been shown to increase adipose tissue blood flow [40] yet GLP-1 pharmacology does not promote weight gain. In several recent reports detailing the acute administration of peptide-based GIPR antagonists optimized for clinical use, it has been postulated that chronic GIPR antagonism can be utilized as a potential therapeutic strategy for the treatment of obesity [32], [35]. These peptide-based GIPR antagonists have been rationally designed through a series of structure-activity relationships and characterized in vitro at the family of receptors [41]. In healthy human volunteers, one such antagonist (hGIP (3–30)-NH2) blocked a majority of the insulinotropic response as a result of the GIP co-infusion [42] and blocked the vasoactivity induced by an acute bolus infusion of GIP [32]. At minimum, these studies clearly demonstrate the ability of this antagonist to block physiological responses attributed to GIP but stop short in demonstrating an effect on body weight. Based on these results, it was speculated that antagonizing GIPR would be of value to improve body weight in humans and is a basis for recent commercialization efforts (WO2016/034186). However, none of these reports study whether chronic therapy with a peptide-based GIPR antagonist induces body weight loss, promotes weight gain or exacerbates HFD-induced weight gain in chronic preclinical pharmacology studies. Such chronic studies are likely hindered because an insufficiently short half-life and limited solubility to support chronic infusion studies. Additionally, species-specific differences in the receptor pharmacological profile also complicate the preclinical study of this analog. This antagonist [hGIP (3–30)-NH2] shows a substantially reduced affinity for the rat GIPR relative to hGIPR [33], [43]. A rat-derived GIP (3–30)NH2 sequence is also limited by a partial agonistic profile at GIPR [31], again highlighting the difficulties in translational research particularly evident with the GIP system.