Efficacy of Bioactive Cyclic Peptides in Rheumatoid Arthritis: Translation from In Vitro to In Vivo Models

Abstract

Using a novel drug discovery technology reported in previous issues of this journal cyclic peptides have been created which are able to down-regulate secretion of inflammatory cytokines, in vitro, by stimulated cells of the macrophage cell line J774. The cytokines in question, TNF-alpha and IL-6, are strongly implicated in etiology of diseases such as rheumatoid arthritis. Studies are reported here using the CAIA animal model for rheumatoid arthritis, which show that the peptides identified are indeed able to impact on inflammation of joints, induced in vivo. The results suggest that these peptides are effective at a dose which could be viable in man, and at which no adverse side effects are evident in the short term.

Peptide-Based Drugs and Drug Delivery Systems

“…Finally, as stressed before, a very important part of the drug development process is a clear transfer from in vitro to in vivo models; striking in vitro effects are no guarantee that these will translate into comparable therapeutic activity in an in vivo experimental model. In this connection, and using a novel drug discovery technology, New et al [ 30 ] created cyclic peptides that are able to down-regulate secretion of inflammatory cytokines both in vitro and in vivo. This holds promise against inflammation-related diseases, such as rheumatoid arthritis, on which cytokines are strongly implicated.…”

Emerging Landscape of In Vitro Models for Assessing Rheumatoid Arthritis Management

“…They permit higher reproducibility and scalability, allowing high-throughput screening for promising therapeutic agents and studying potential drug candidates. 65 The in vitro models can also be considered costeffective and ethical and permit the manipulation of specific variables during the studies, such as the cell types as well as the concentration of certain substances, which may not always be possible in animal experiments. 66 The in vitro models also permit a rapid and accurate evaluation of the activity and toxicity of nanomaterials.…”

“…The in vitro models offer better predictability and translatability of the findings into clinical settings, bridging the gap between laboratory research and clinical practice and making them indispensable for research in the current scenario, particularly in the case of RA. 65 For example, the in vitro studies have effectively utilized the synovial fluid-derived fibroblast-like synoviocytes to study the inflammatory process in RA, giving deep insights into the pathophysiology of the disease and facilitating the drug discovery processes. 67 In RA research, the in vitro models have significantly improved in the past decades and are now considered indispensable in research, offering a controlled, reproducible, scalable, translatable, ethical, and cost-effective platform, closely simulating the human physiological conditions and the disease microenvironment, and can give valuable insights regarding the pathophysiology and mechanisms of the disease, permitting high throughput screening, and development of promising therapeutic strategies and even permitting precision medicine approaches.…”

Controversy of Peptide Cyclization from Tripeptide

“…In addition, some α-cyclic tripeptides also synthesized as the inhibitors for HMG-CoA reductase [ 22 ]. As a continuation of natural cyclopeptide synthesis, we attempted to synthesize a rare example of naturally occurring marine α-cyclic tripeptide, cyclo (Gly- l -Pro- l -Glu) 1 [ 8 ], for applications in vivo as it is more permeable and more resistant to degradation by digestive proteases [ 23 ]. When rendered into its linear form, Gly- l -Pro- l- Glu (GPE) is the N -terminal sequence of insulin-like growth factor (IGF-1) [ 24 , 25 ].…”