Carboxylate Surrogates Enhance the Antimycobacterial Activity of UDP-Galactopyranose Mutase Probes

Winton, Valerie J.; Aldrich, Claudia; Kiessling, Laura L.

doi:10.1021/acsinfecdis.6b00021

Cited by 18 publications

(25 citation statements)

References 56 publications

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“…51 SAR studies of UGM inhibitors, however, indicate the carboxylate negative charge is critical for potency. 52 We therefore sought a carboxylate mimetic likely to evade detoxification enzymes. We previously found N -acylsulfonamide groups were effective carboxylate surrogates, as they are anionic at physiological pH values.…”

Section: Resultsmentioning

confidence: 99%

“…52 These analogs were tested for their ability to impede the catalytic activity of CeUGM. 22 Carboxylate-containing compounds 1 and 11 were active, but the corresponding methyl esters (compounds 10 and 14 ) were significantly less potent.…”

Section: Resultsmentioning

confidence: 99%

“…These results support our previous findings that the N -acylsulfonamide group functions as an effective carboxylate surrogate. 52 (Table 1). The most potent inhibitor identified was the chlorophenylsulfonamide 8 (IC 50 = 0.7 ± 0.3 µM).…”

Section: Resultsmentioning

confidence: 99%

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Deleterious Consequences of UDP-Galactopyranose Mutase Inhibition for Nematodes

et al. 2017

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Parasitic nematodes pose a serious threat to agriculture, livestock, and human health. Increasing resistance to anti-parasitic agents underscores the need to replenish our anthelmintic arsenal. The non-pathogenic Caenorhabditis elegans, which serves as an effective model of parasitic helminths, has been used to search for new anthelmintic leads. We previously reported small-molecule inhibitors of the essential C. elegans protein UDP-galactopyranose mutase (UGM or Glf). This enzyme is required for the generation of galactofuranose (Galf)-containing glycans and is needed in nematodes for proper cuticle formation. Though our first-generation inhibitors were effective in vitro, they elicited no phenotypic effects. These findings are consistent with the known difficulty of targeting nematodes. C. elegans is recalcitrant to pharmacological modulation; typically, less than 0.02% of small molecules elicit a phenotypic effect, even at 40 µM. We postulated the lack of activity of the UGM inhibitors was due to their carboxylic acid group, which can be exploited by nematodes for detoxification. We therefore tested whether replacement of the carboxylate with an N-acylsulfonamide surrogate would result in active compounds. UGM inhibitors with the carboxylate mimetic can phenocopy the deleterious consequences of UGM depletion in C. elegans. These findings support the use of UGM inhibitors as anthelmintic agents. They also outline a strategy to render small-molecule carboxylates more effective against nematodes.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Deleterious Consequences of UDP-Galactopyranose Mutase Inhibition for Nematodes

et al. 2017

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“…Indeed, this possibility is supported by the increased efficacy of small-molecule inhibitors in which the carboxylate is replaced by a larger N -acylsulfonamide group. 16 …”

Section: Discussionmentioning

confidence: 99%

Conformational Control of UDP-Galactopyranose Mutase Inhibition

et al. 2017

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UDP-galactopyranose mutase (Glf or UGM) catalyzes the formation of uridine 5′-diphosphate-α-D-galactofuranose (UDP-Galf) from UDP-galactopyranose (UDP-Galp). The enzyme is required for the production of Galf-containing glycans. UGM is absent in mammals, but members of the Corynebacterineae suborder require UGM for cell envelope biosynthesis. The need for UGM in some pathogens has prompted the search for inhibitors that could serve as antibiotic leads. Optimizing inhibitor potency, however, has been challenging. The UGM from Klebsiella pneumoniae (KpUGM), which is not required for viability, is more effectively impeded by small-molecule inhibitors than are essential UGMs from species such as Mycobacterium tuberculosis or Corynebacterium diphtheriae. Why KpUGM is more susceptible to inhibition than other orthologs is not clear. One potential source of difference is UGM ortholog conformation. We previously determined a structure of CdUGM bound to a triazolothiadiazine inhibitor in the open form, but it was unclear whether the small molecule inhibitor bound this form or to the closed form. By varying the terminal tag (CdUGM-His6 and GSG-CdUGM), we crystallized CdUGM to capture the enzyme in different conformations. These structures reveal a pocket in the active site that can be exploited to augment inhibitor affinity. Moreover, they suggest the inhibitor binds the open form of most prokaryotic UGMs but can bind the closed form of KpUGM. This model and the structures suggest strategies to optimize inhibitor potency by exploiting UGM conformational flexibility.

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“…Natural (e.g., antibodies) and synthetic multivalent molecular peptides[1-3], peptidomimetics (such as peptoids[4-6]), carbohydrates[7-9], and small molecules[10, 11], present multiple copies of a receptor-binding element, which can therefore bind with high avidity and specificity. [9, 12-17] These can interact with receptors via chelating effects, receptor clustering, subsite binding, and statistical rebinding, all of which can lead to an improved affinity.…”

Section: Introductionmentioning

confidence: 99%

A unique mid-sequence linker used to multimerize the lipid-phosphatidylserine (PS) binding peptide-peptoid hybrid PPS1

Shukla

Manarang

Udugamasooriya

2017

European Journal of Medicinal Chemistry

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Ligand multimerizations enhance the binding affinity towards cell surface biomarkers through their avidity effects. Typical linkers connect individual monomeric ligand moieties from one end (e.g., C- or N-terminus of a peptide) and exclusively target protein receptors. The lipid phosphatidylserine (PS) is normally present on the cytoplasmic side of the eukaryotic cell membrane, but in tumors and tumor endothelial cells, this negatively charged PS flips to the outer layer. We recently reported a PS binding peptide-peptoid hybrid (PPS1) that has distinct positively charged and hydrophobic residue-containing regions. The PPS1 monomer is inactive, and upon C-terminal dimerization (PPS1D1), it triggers cytotoxicity. In the current study, a unique series of PPS1 multimeric derivatives were synthesized by switching the linker from the C-terminus to an internal position. The unimportant fourth residue (N-lys) from the C-terminus was utilized to build the linker. The synthesis strategy was developed employing variations of (I) the linker size, (II) the number of positively charged residues, and (III) the number of hydrophobic regions. Cytotoxicity of these new derivatives on HCC4017 lung cancer cells showed that a minimum of two hydrophobic regions was important to retain the activity and that the shortest linker length was optimal for activity.

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Carboxylate Surrogates Enhance the Antimycobacterial Activity of UDP-Galactopyranose Mutase Probes

Cited by 18 publications

References 56 publications

Deleterious Consequences of UDP-Galactopyranose Mutase Inhibition for Nematodes

Deleterious Consequences of UDP-Galactopyranose Mutase Inhibition for Nematodes

Conformational Control of UDP-Galactopyranose Mutase Inhibition

A unique mid-sequence linker used to multimerize the lipid-phosphatidylserine (PS) binding peptide-peptoid hybrid PPS1

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