9 research outputs found
Cardioprotection by systemic dosing of thymosin beta four following ischemic myocardial injury
Thymosin beta 4 (TĪ²4) was previously shown to reduce infarct size and improve contractile performance in chronic myocardial ischemic injury via two phases of action: an acute phase, just after injury, when TĪ²4 preserves ischemic myocardium via antiapoptotic or anti-inflammatory mechanisms; and a chronic phase, when TĪ²4 activates the growth of vascular or cardiac progenitor cells. In order to differentiate between the effects of TĪ²4 during the acute and during the chronic phases, and also in order to obtain detailed hemodynamic and biomarker data on the effects of TĪ²4 treatment suitable for use in clinical studies, we tested TĪ²4 in a rat model of chronic myocardial ischemia using two dosing regimens: short term dosing (TĪ²4 administered only during the first 3 days following injury), and long term dosing (TĪ²4 administered during the first 3 days following injury and also every third day until the end of the study). TĪ²4 administered throughout the study reduced infarct size and resulted in significant improvements in hemodynamic performance; however, chamber volumes and ejection fractions were not significantly improved. TĪ²4 administered only during the first 3 days following injury tended to reduce infarct size, chamber volumes and improve hemodynamic performance. Plasma biomarkers of myocyte injury were significantly reduced by TĪ²4 treatment during the acute injury period, and plasma ANP levels were significantly reduced in both dosing groups. Surprisingly, neither acute nor chronic TĪ²4 treatment significantly increased blood vessel density in peri-infarct regions. These results suggest the following: repeated dosing may be required to achieve clinically measureable improvements in cardiac function post-myocardial infarction (MI); improvement in cardiac function may be observed in the absence of a high degree of angiogenesis; and that plasma biomarkers of cardiac function and myocardial injury are sensitive pharmacodynamic biomarkers of the effects of TĪ²4
Mechano Growth Factor peptide (MGF), the COOH terminus of unprocessed Insulin-like growth factor 1 (IGF-1), has no apparent effect on muscle myoblasts or primary muscle stem cells
A splice form of IGF-1, IGF-1Eb, is upregulated after exercise or injury. Physiological responses have been ascribed to the 24 amino acid COOH-terminal peptide which is cleaved from the NH3 terminal 70 amino acid mature IGF-1 protein. This COOH-terminal peptide was termed āmechano-growth factorā (MGF). Activities claimed for the MGF peptide included enhancing muscle satellite cell proliferation and delaying myoblast fusion. As such, MGF could represent a promising strategy to improve muscle regeneration. Thus at our two pharmaceutical companies we attempted to reproduce the claimed effect of MGF peptides on human and mouse muscle myoblast proliferation and differentiation in vitro. Concentrations of peptide up to 500 ng/ml failed to increase the proliferation of C2C12 cells or primary human skeletal muscle myoblasts. In contrast, all cell types exhibited a proliferative response to mature IGF-1 or full-length IGF-1Eb. MGF also failed to inhibit the differentiation of myoblasts into myotubes. To address whether the response to MGF was lost in these tissue culture lines, we measured proliferation and differentiation of primary mouse skeletal muscle stem cells exposed to MGF. This too failed to demonstrate a significant effect. Finally, we tested whether MGF could alter a separate documented in vitro effect of the peptide, activation of pERK, but not pAkt in cardiac myocytes. While a robust response to IGF-1 was observed, there were no demonstrated activating responses from the native or a stabilized MGF peptide. These results call in to question whether there is a physiological role for MGF
<i>In vivo</i>Ā half-life extension of BMP1/TLL metalloproteinase inhibitors using small-molecule human serum albumin binders
Reducing the required frequence of drug dosing can improve the adherence of patients to chronic treatments. Hence, drugs with longer half-lives are highly desirable. One of the most promising approaches to extend the half-life of drugs is conjugation to human serum albumin (HSA). In this work, we describe the use of , a small-molecule noncovalent HSA binder, to extend the half-life and pharmacology of small-molecule BMP1/TLL inhibitors in humanized mice (HSA KI/KI). A series of conjugates of with BMP1/TLL inhibitors were prepared. In particular, showed good solubility and a half-life extension of >20-fold versus the parent molecule in the HSA KI/KI mice, reaching half-lives of >48 h with maintained maximal inhibition of plasma BMP1/TLL. The same conjugate showed a half-life of only 3 h in the wild-type mice, suggesting that the half-life extension was principally due to specific interactions with HSA. It is envisioned that conjugation to should be applicable to a wide range of small molecule or peptide drugs with short half-lives. In this context, AlbuBinders represent a viable alternative to existing half-life extension technologies