Inhibition of Golgi Mannosidase II with Mannostatin A Analogues: Synthesis, Biological Evaluation, and Structure–Activity Relationship Studies

Abstract

Mannostatin and aminocyclopentitetrol analogues with various substitutions at the amino function were synthesized. These compounds were tested as inhibitors of human Golgi and lysosomal alpha-mannosidases. Modification of the amine of mannostatin had only marginal effects, whereas similar modifications of aminocyclopentitetrol led to significantly improved inhibitors. Ab initio calculations and molecular docking studies were employed to rationalize the results. It was found that mannostatin and aminocyclopentitretrol could bind to Golgi alpha-mannosidase II in a similar mode to that of the known inhibitor swainsonine. However, due to the flexibility of the five-membered rings of these compounds, additional low-energy binding modes could be adopted. These binding modes may be relevant for the improved activities of the benzyl-substituted compounds. The thiomethyl moiety of mannostatin was predicted to make favorable hydrophobic interactions with Arg228 and Tyr727 that would possibly account for its greater inhibitory activity.

The Molecular Basis of Inhibition of Golgi α‐Mannosidase II by Mannostatin A

“…Furthermore, analyses of the various structures indicate that differences in the hydration of the protein-binding site, is an important factor for plasticity as well as selectivity of inhibitor binding. In retrospect, it is not surprising that the active site of GMII has proven difficult to model accurately, [35, 36] since small differences in inhibitor chemistry result in large differences in inhibitor potency.…”

Substrate Distortion by a Lichenase Highlights the Different Conformational Itineraries Harnessed by Related Glycoside Hydrolases

“…This leads to the possibility of specific, targeted inhibition of clinically relevant enzymes. In this context, a large number of mannosidase inhibitors have been proposed in recent times with amidines, [25] pyridines [26] and isoquinuclidines, [27] and functionalized mannostatin and aminocyclopentitetrol analogues [21] that are notable for their binding to mannosidases.…”

“…In this light, the inhibition of Golgi amannosidases is emerging as a potential anti-cancer target. [21][22][23] Mannosidase II action is a prerequisite for the action of Golgi b-1,6-N-acetylglucosaminyltransferase V (MGAT5). This latter enzyme plays a key role in malignancy and cancer progression, with MGAT5-deficient mice exhibiting suppressed tumor growth and metastasis.…”

Elevated plasma high-mobility group box 1 protein is a potential marker for neuromyelitis optica

“…IFN-c has been reported to induce HMGB1 secretion (Strachan et al, 2008), and increased HMGB1 plasma level correlated with active inflammation in our patients. HMGB1 has been reported to activate human neutrophils to produce proinflammatory mediators such as TNF-a, IL-1b, and IL-8 (Li et al, 2004). HMGB1 itself also acts as an immunostimulatory signal to induce maturation of dendritic cells and the secretion of proinflammatory cytokines including TNF-a, IL-1a, IL-17, IL-8, and IL-12 (Gupta et al, 2004;Marioni et al, 2010).…”