Development of carbon monoxide-releasing molecules conjugated to polysaccharides (glyco-CORMs) for delivering CO during obesity

Développement de molécules libératrices de monoxyde de carbone conjuguées à des polysaccharides (glyco-CORM) pour délivrer du CO lors de l'obésité

Shruti Mohan (1) , Louis-Antoine Barel (2) , Djamal Eddine Benrahla (1) , Bernard Do (3, 4) , Qiyue Mao (5) , Hiroaki Kitagishi (5) , Michael Rivard (2) , Roberto Motterlini (1) , Roberta Foresti (1)

1 IMRB - Institut Mondor de Recherche Biomédicale
2 ICMPE - Institut de Chimie et des Matériaux Paris-Est
3 Groupe matériaux et santé
4 CHU Henri Mondor [Créteil]
5 Doshisha University [Kyoto]

Metal carbonyls have been developed as carbon monoxide-releasing molecules (CO-RMs) to deliver CO for therapeutic purposes. The manganese-based CORM-401 has been recently reported to exert beneficial effects in obese animals by reducing body weight gain, improving glucose metabolism and reprogramming adipose tissue towards a healthy phenotype. Here, we report on the synthesis and characterization of glyco-CORMs, obtained by grafting manganese carbonyls on dextrans (70 and 40 kDa), based on the fact that polysaccharides facilitate the targeting of drugs to adipose tissue. We found that glyco-CORMs efficiently deliver CO to cells in vitro with higher CO accumulation in adipocytes compared to other cell types. Oral administration of two selected glyco-CORMs (5b and 6b) resulted in CO accumulation in various organs, including adipose tissue. In addition, glyco-CORM 6b administered for eight weeks elicited anti-obesity and positive metabolic effects in mice fed a high fat diet. Our study highlights the feasibility of creating carriers with multiple functionalized CORMs .

Mots clés: Carbon monoxide; Carbon monoxide-releasing molecules (CO-RMs); Obesity; Adipocytes; Macrophages

Domaines: Chimie thérapeutique; Endocrinologie et métabolisme

Shruti Mohan, Louis-Antoine Barel, Djamal Eddine Benrahla, Bernard Do, Qiyue Mao, et al.. Development of carbon monoxide-releasing molecules conjugated to polysaccharides (glyco-CORMs) for delivering CO during obesity. Pharmacological Research, 2023, 191, pp.106770. ⟨10.1016/j.phrs.2023.106770⟩. ⟨hal-04168490⟩