Novel approaches to glycomimetic design: development of small molecular weight lectin antagonists

ABSTRACT

Introduction: The direct binding of carbohydrates or those presented on glycoproteins or glycolipids to proteins is the primary effector of many biological responses. One class of carbohydrate-binding proteins, lectins are important in all forms of life. Their functions in animals include regulating cell adhesion, glycoprotein synthesis, metabolism, and mediating immune system response while in bacteria and viruses a lectin-mediated carbohydrate–protein interaction between host cells and the pathogen initiates pathogenesis of the infection.

Areas covered: In this review, the authors outline the structural and functional pathogenesis of lectins from bacteria, amoeba, and humans. Mimics of a carbohydrate are referred to as glycomimetics, which are much smaller in molecular weight and are devised to mimic the key binding interactions of the carbohydrate while also allowing additional contacts with the lectin. This article emphasizes the various approaches used over the past 10–15 years in the rational design of glycomimetic ligands.

Expert opinion: Medicinal chemistry efforts enabled by X-ray structural biology have identified small-molecule glycomimetic lectin antagonists that have entered or are nearing clinical trials. A common theme in these strategies is the use of biaryl ring systems to emulate the carbohydrate interactions with the lectin.

KEYWORDS:

• bacterial adhesin
• lectin
• structure-based drug design (SBDD)
• virulence factor
• glycomimetic
• carbohydrate
• antibacterial
• glycoside
• antibiotic resistance
• infectious disease

Article highlights

• The large plethora of medicinal chemistry strategies in the design and synthesis of potent and selective multivalent and monovalent glycomimetic inhibitors have been accomplished in the past last 10–15 years. These studies have been made possible from the X-ray structure-based drug design and development of synthetic glycomimetic ligands of lectins.

• Lectins are carbohydrate-binding proteins that are found in most organisms ranging from viruses and bacteria to other parasites and to plants and mammals including humans.

• Multivalent and glycodendrimer ligands dramatically increase inhibitory potencies for LecA, LecB, AB₅ toxins, galectins, DC-SIGN, and Siglecs.

• Modern rational design approaches have successfully identified mannoside and galactoside monovalent glycomimetics as high-affinity lectin antagonists. A large number of these ligands contain multiple aromatic rings as the aglycone such as a biphenyl group which emulate the native interactions of sugars with these lectins.

• To date, only a few glycomimetic compounds have been approved as drugs. In some cases, the design of glycomimetic ligands is challenging due to the presence of multiple sugar-binding pockets or the large water-exposed surface surrounding the lectin sugar-binding pocket requiring innovative drug design and medicinal chemistry approaches.

• Recent approaches have identified small-molecule glycomimetic lectin antagonists that have entered or are nearing clinical trials.

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Declaration of interest

J Janetka is a co-founder, board member, consultant and owner of shares in Fimbrion Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.