Skip to main content
NCBI home page
ACS Medicinal Chemistry Letters logoLink to ACS Medicinal Chemistry Letters
. 2022 May 10;13(6):935–942. doi: 10.1021/acsmedchemlett.2c00067

Drug-like Inhibitors of DC-SIGN Based on a Quinolone Scaffold

Hengxi Zhang †,‡,∇,⊗, Ondřej Daněk §, Dmytro Makarov §, Stanislav Rádl §,∥, Dongyoon Kim †,∇,⊗, Jiří Ledvinka §, Kristýna Vychodilová ⊥, Jan Hlaváč #, Jonathan Lefèbre ∇,⊗, Maxime Denis ∇,⊗, Christoph Rademacher †,‡,∇,⊗,*, Petra Ménová §,*
PMCID: PMC9190040  PMID: 35707152

Abstract

graphic file with name ml2c00067_0007.jpg

DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin) is a pattern recognition receptor expressed on immune cells and involved in the recognition of carbohydrate signatures present on various pathogens, including HIV, Ebola, and SARS-CoV-2. Therefore, developing inhibitors blocking the carbohydrate-binding site of DC-SIGN could generate a valuable tool to investigate the role of this receptor in several infectious diseases. Herein, we performed a fragment-based ligand design using 4-quinolone as a scaffold. We synthesized a library of 61 compounds, performed a screening against DC-SIGN using an STD reporter assay, and validated these data using protein-based 1H–15N HSQC NMR. Based on the structure–activity relationship data, we demonstrate that ethoxycarbonyl or dimethylaminocarbonyl in position 2 or 3 is favorable for the DC-SIGN binding activity, especially in combination with fluorine, ethoxycarbonyl, or dimethylaminocarbonyl in position 7 or 8. Furthermore, we demonstrate that these quinolones can allosterically modulate the carbohydrate binding site, which offers an alternative approach toward this challenging protein target.

Keywords: Fragment-based ligand design, Lectin, DC-SIGN, NMR, Structure−activity relationship, 4-Quinolone

C-type lectin receptors (CLRs) constitute the largest and most diverse family of glycan binding proteins in mammals.1 Many members of this family are selectively expressed on immune cells, where they serve as pattern recognition receptors and facilitate the distinction between entities of endogenous and exogenous origin. Subsequent initiation of endocytosis and signaling cascades modulate the immunological output and antigen presentation, rendering CLRs pivotal components of the innate and adaptive immune response. Spurred by the accumulating evidence for their physiological and pathophysiological relevance, several CLRs have been recognized as promising targets for drug discovery.2 Prominent examples include Mincle,3 Langerin,4 mannose receptor,5 LOX-1,6 ASGPR,7 Dec205,8,9 and DC-SIGN.

DC-SIGN is a mannose- and fucose-binding endocytic receptor that is expressed by antigen presenting cells and has been identified as a candidate for targeted delivery of prophylactic vaccines as well as immunomodulatory drugs.10 Moreover, due to its role as entry point for pathogens such as HIV,11 Ebola,12 Dengue,13 and SARS-CoV-2,14 DC-SIGN-specific inhibitors have been suggested as anti-infectives.15,16

Despite growing pharmaceutical interest, the discovery of potent inhibitors targeting DC-SIGN, as well as CLRs in general, has been hampered by the hydrophilic and shallow nature of the carbohydrate binding site (CBS), which results in low intrinsic affinities for its carbohydrate ligands.2,17 For example, the affinity of DC-SIGN for its monovalent carbohydrate ligand, mannose, is 3.5 mM.15 Furthermore, since carbohydrates do not bear hydrophobic groups and mainly rely on hydrogen bonding with the CBS, their pharmacological properties are insufficient to consider them as drug-like.2 The main driver of the mammalian receptor–glycan interaction is multivalency, which is mediated through the presentation of multiple copies of the glycan ligand and by multimerization of the receptor. In DC-SIGN, the extracellular domain (ECD) contains a neck domain that projects the carbohydrate recognition domain (CRD) away from the cell surface and allows for tetramerization and clustering of the receptor. This increases the affinity from the low millimolar range for a monovalent interaction into the nanomolar range for multivalent carbohydrate recognition and has been exploited in delivery approaches that mimic the multivalent presentation and spatial organization of natural DC-SIGN-binding glycans.18 However, because of the high promiscuity of the CLR–carbohydrate interaction, low specificity for mono- and oligosaccharides is observed. In this context, rationally designed carbohydrate analogs, so-called glycomimetics, have been developed and proved to be a good starting point for a specific and high-affinity alternative to natural DC-SIGN ligands. Several recent reports have focused on targeting the extended surface of the CBS with drug-like fragments conjugated to a core mannose moiety.19−27 Nevertheless, the development and synthesis of high-affinity glycomimetics is challenging and relies on additional binding pockets in proximity to the CBS.

We and others have screened and identified fragment-sized and drug-like compounds showing activity against DC-SIGN.28−31 Non-carbohydrate small-molecule inhibitors of DC-SIGN based on pyrazolone, thiazole, or quinoxalinone have been reported to block not only DC-SIGN–carbohydrate interactions but also DC-SIGN-mediated cell adhesion.31 Additionally, we have provided several new scaffolds such as benzoisoxazoles and oxazolinones from 19F NMR and SPR screening.30 Examples of published non-carbohydrate inhibitors are shown in Table S1.31,32 Previously identified quinoxalinone-based fragments (compounds I–III, Table S1) have a high ligand efficiency (LE),47 but the affinity for DC-SIGN is still low and needs to be improved. More complex quinoxalinone-based inhibitors (compounds IV–VIII, Table S1) show a high affinity with IC50 values in the low micromolar range (1.6–10 μM), but their solubility and LE are relatively low. Based on these insights and our recent discovery that DC-SIGN offers several secondary binding sites, we explored the utility of these sites for allosteric modulation.30,33 Allosteric inhibitors provide pharmacological benefits such as improved selectivity, due to the lower evolutionary conservation of their binding sites, and physicochemical properties compared to orthosteric ligands.33,34 We found that the fragments that show binding affinity share common features: a bicyclic core with a heteroatom and a carbonyl group. Based on these findings, we proposed 4-quinolone as a potential structurally related binder.

Quinolones are prominent scaffolds in medicinal chemistry. Since the discovery of their antibacterial properties in the early 1960s, four generations of quinolone antibiotics have been introduced to the market.35 While the early quinolones were only active against Gram-negative bacteria and displayed numerous adverse side effects, the third- and fourth-generation quinolone antibiotics are effective against both Gram-negative and Gram-positive bacteria, and their toxicity is reduced. Ciprofloxacin, levofloxacin, and moxifloxacin are among the most widely used antibiotics worldwide and are listed on the WHO Model List of Essential Medicines. Recently, some quinolones have been shown to be active against infectious diseases such as tuberculosis,36 malaria,37 hepatitis C,38 and HIV39 or have anticancer40 or antidiabetic41 properties.

Here, we explore the structure–activity relationships (SARs) of the quinolone scaffold as a promising starting point for inhibitors against DC-SIGN.

The cyclization of the intermediates to form the quinolone core can be achieved by heating with an acid (polyphosphoric acid or Eaton’s reagent—a mixture of methanesulfonic acid and phosphorus pentoxide) or by thermally induced cyclization. While the former approach led to low yields and low purity, thermal cyclization, achieved by heating the intermediate in a high-boiling point solvent (diphenyl ether or Dowtherm A), afforded the desired compounds in both higher yields and better purity. When starting from m-substituted anilines (Scheme 1A–C), a small amount of the 5-substituted quinolone was formed together with the major 7-substituted isomer, which was recovered by crystallization. The quinolone scaffold was further modified by standard synthetic procedures: ester-to-amide substitution, Steglich-type amide coupling, aromatic nucleophilic substitution, and attachment of an amino acid residue by solid-phase synthesis. The synthetic procedures for compounds 1–26 and S1–S36, as well as their NMR spectra, can be found in the Supporting Information.

Scheme 1. Synthesis of 4-Quinolones Used in the Structure–Activity Relationship (SAR) Study.

Scheme 1

Open in a new tab

(A) Reaction of aniline with diethyl ethoxymethylenemalonate, followed by thermal or acid-catalyzed cyclization. (B) Reaction of aniline with methyl 3-(dimethylamino)-2-(phenylsulfonyl)acrylate, followed by thermal cyclization. (C) Addition of aniline to diethyl but-2-ynedioate, followed by thermal cyclization. (D) Alkylation of anthranilic acid with bromoacetophenone, followed by acid-catalyzed cyclization.

Inspired by the previously reported high-affinity non-carbohydrate DC-SIGN inhibitors, we designed a focused quinolone-based library consisting of compounds 1–6 (Table 1 and Table S2). To enable rapid and sensitive screening against DC-SIGN, we chose reporter-based competition experiments based on 1H saturation transfer difference (STD) NMR.15 This method is used to screen small to medium-sized compound libraries for ligands with a wider range of binding affinities, including high-affinity inhibitors, by detecting signal intensity changes of a STD reporter molecule. We identified quinolone 1 as a suitable reporter molecule due to its high solubility, relatively weak binding affinity (KD = 2.9 ± 0.7 mM, Figure 1A), and high signal-to-noise ratio in STD NMR experiments (Figure 1B). An epitope map was derived from STD build-up experiments that suggested that H8 was in close contact with the receptor site and indicated a one-site binding mechanism (Figure 1B).42 In contrast, the carboxamide experienced less saturation transfer, suggesting positioning away from the protein. For the STD NMR reporter assay, we chose four aromatic resonance indicator peaks (resonances 2, 5, 7, and 8) because of their high signal-to-noise ratio and dispersity (Figure 1B).

Table 1. Affinity Values of Selected Compounds Evaluated by HSQC NMR and STD NMRa.

graphic file with name ml2c00067_0004.jpg

Open in a new tab
a

NB = no binding.

Figure 1.

Figure 1

Open in a new tab

Binding mode and affinity analysis of reporter molecule 1 by ITC and STD NMR. (A) ITC thermogram and reaction heats of compound 1 interacting with DC-SIGN. The binding affinity KD is 2.9 ± 0.7 mM (n = 1). (B) STD NMR epitope map of compound 1 and four peaks that served as “indicator peaks” during competition experiments as observed in the STD NMR difference spectrum (saturation time 2.0 s, relaxation delay 2.0 s, 256 scans).

Next, we screened the quinolone library using the STD NMR reporter assay with compound 1 as the reporter molecule. Figure 2 shows an example of an STD NMR spectrum of the reporter in the absence and presence of competitor 7. Upon the addition of 200 μM competitor 7 into 20 μM DC-SIGN ECD, the STD signal intensities of the indicator peaks were reduced by 20%, suggesting that the reporter and the competitor share the same binding site, allowing for competition (Figure 2). Based on the relationship between the reduction of the STD effect and the binding affinity,43 we derived the binding affinity by averaging the three high signal-to-noise resonances (Figure 2A,B). To verify binding to DC-SIGN and the derived affinities of compounds with good solubility (4, 7, 8, 9, and 10), we analyzed chemical shift perturbations (CSPs) in 1H–15N HSQC NMR experiments using 15N-labeled DC-SIGN CRD. In the 1H–15N HSQC NMR study, we used 100 μM protein to be titrated with different concentrations of those fragments that were highly soluble, so that the derived KD value in the high micromolar range could confirm the results of the STD NMR. Representative results are shown in Table 1, and the CSP fingerprints are shown in Figures S3–S6. All studied compounds show the same binding affinity in both the 1H–15N HSQC NMR titration and the STD reporter assay. These results indicate that the STD reporter assay is reliable and can be used for the library screening against DC-SIGN. The overall SAR data are summarized in Table 2.

Figure 2.

Figure 2

Open in a new tab

Example of a competition STD NMR experiment showing the displacement of compound 1 due to compound 7 binding to DC-SIGN. (A) STD NMR spectrum is recorded with a saturation time of tsat = 2 s at 850 μM reporter molecule 1 and 20 μM protein concentration. STD spectrum of reporter 1 (850 μM) used as a reference (resonances 2, 5, 7, and 8), in the presence of DC-SIGN, is shown in black; STD spectrum of 200 μM competitor 7 added to a mixture of reporter 1 and DC-SIGN is shown in gray. The spectra show that the STD signal intensities of reporter 1 were reduced after the addition of competitor 7 (signal reduced by 20%). (B) Example plot of binding affinity Ki against the ratio between STD(I) and STD(0) when the ligand concentration is 200 μM. STD(0) and STD(I) are the signal intensities of the reporter molecule prior to and after the addition of the competitor, respectively.47 Concentrations used: ligand 200 μM, protein 20 μM, competitor 850 μM.

Table 2. Initial Structure–Activity Relationship (SAR) Study of Quinolones against DC-SIGNa.

graphic file with name ml2c00067_0005.jpg

graphic file with name ml2c00067_0006.jpg

Open in a new tab
a

LE = ligand efficiency;47 NB = no binding.

The six initially chosen quinolones (1–6) showed differential binding activities. While no binding was detected for compounds 3 and 6, all other compounds showed affinities in the low millimolar to upper micromolar range (3.0–0.2 mM).

Next, we evaluated the influence of different substitution patterns on the activity of the quinolone scaffold. We started by modifying position 3. The presence of the dimethylaminocarbonyl group in position 3 of compound 1 resulted in binding activity in the millimolar range. In contrast, hydrolysis of the amide to a free carboxylic acid (compound 11) led to a complete loss of activity. Similarly, the introduction of bulky substituents, morpholinocarbonyl and phenyloxycarbonyl (compounds 12 and 13), also led to the loss of binding activity. While the phenylsulfonyl group in position 3 in quinolone 2 afforded a compound with millimolar binding affinity, no binding activity was detected for compounds 15 and 17, bearing carboxyl and piperidinylcarbonyl groups, respectively. We also prepared a series of 3-phenylsulfonyl-substituted derivatives. The incorporation of a strongly electron-withdrawing dimethylaminocarbonyl group (compound 18) instead of a moderately electron-withdrawing fluorine (compound 2) increased the binding affinity more than 6-fold (KD = 0.3 mM and KD = 1.9 mM, respectively). All other prepared 3-phenylsulfonyl derivatives were not soluble enough to evaluate their affinity (compounds S1–S7).

Accordingly, the dimethylaminocarbonyl group in position 3 was fixed, and we further explored the influence of substitution in positions 6, 7, and 8. The incorporation of an electron-donating dimethylamino group (compound 10) instead of the electron-withdrawing fluorine (compound 1) in position 6 led to loss of affinity. The introduction of a bulkier and strongly electron-withdrawing dimethylaminosulfonyl group in position 6 (compound 14) also resulted in undetectable binding activity. In contrast, the introduction of a dimethylamino group in position 7 instead of the fluorine in position 6 (compound 9) led to a 7-fold increase in binding affinity (KD = 0.4 mM). Furthermore, positioning the fluorine atom in position 8 instead of 6 (compound 8) increased the binding affinity almost 10-fold (KD = 0.3 mM).

We then focused on compounds bearing an ethoxycarbonyl group in position 3. While compounds 4, 16, and 21 all showed sub-millimolar affinities (KD = 0.1–0.3 mM), compounds S9–S11 showed no binding, and compounds S13–S20 were not soluble enough to evaluate their binding affinities. Replacement of the ethoxycarbonyl group with benzyloxycarbonyl led to compounds with limited solubility (compounds S22–S25). Hydrolysis of the ethoxycarbonyl group to free carboxyl usually led to compounds with no binding affinity (compounds 11, 15, 23, and S21). This hydrolysis led to a more than 10 times lower affinity of the otherwise unsubstituted quinolone (compare compounds 4 and 5). Interestingly, the free acid with the 6-piperidinylsulfonyl group showed a significant affinity, with KD = 0.5 mM. It is also interesting to note that ester 16 showed a remarkable affinity, while amide 10 did not bind at all.

Introduction of the ethoxycarbonyl group in position 2 rather than 3 afforded compounds with increased solubility. Quinolones bearing substituents in position 6 (compounds 3, 19, and 20) showed no affinity. In contrast, 8-substituted derivatives 7 and 22 both showed sub-millimolar affinities.

Considering the sub-millimolar binding affinity values of compounds 7, 8, 21, and 22, we identified position 8 as an interesting starting point for further fragment growing or introduction of bulkier substituents.

Finally, we prepared a series of 11 2-aryl-3-hydroxyquinolones. Of these, four compounds did not show sufficient solubility (S32–S35), and five (S26–S31) did not show any binding. Only quinolones 6 and 26 showed very weak STD NMR peaks, which may indicate their low binding affinity for DC-SIGN. Hence, we excluded 2-aryl-3-hydroxyquinolones from further optimization.

To conclude the SAR study, 2-aryl-3-hydroxy derivatives did not prove to be good leads because most of the studied compounds lack binding affinity. Solubility is a major issue for many 3-substituted derivatives (3-phenylsulfonyl, 3-benzyloxycarbonyl, and several 3-ethoxycarbonyls). 2-Ethoxycarbonyl-substituted quinolones showed a better solubility and, in some cases, also improved binding affinity. With a few exceptions, substitution in position 6 leads to loss of affinity. We have not observed any clear trend with regard to substitution in position 7. In contrast, substitution in position 8 seems to be beneficial for activity. Overall, we demonstrated that ethoxycarbonyl or dimethylaminocarbonyl in position 2 or 3 promotes DC-SIGN binding activity, particularly when combined with fluorine, ethoxycarbonyl, or dimethylaminocarbonyl in position 7 or 8.

The HSQC NMR data do not show CSPs in the CBS but in other sites of DC-SIGN, suggesting that quinolones bind to a secondary binding site (Figures S3–S6). This is in line with our previous observation that many heterocyclic compounds bind to secondary sites of DC-SIGN.30 Therefore, we further explored the competition of quinolones with carbohydrate ligands using a previously established 19F reporter displacement NMR assay (RDA).44 Here, we monitored the transversal relaxation rate R2,obs of the reporter 2-deoxy-2-trifluoroacetamido-α-d-mannoside (S36). Since the affinity of this molecule is weak (KD = 1.9 ± 0.9 mM) (Table S1), it could potentially be displaced by quinolone competitors. First, we verified the assay using mannose as a reference (Figure S1A).45 Since mannose and S36 share the same binding site, a full competition curve can be observed, and the affinity of mannose (Ki = 2.4 ± 0.8 mM) is in line with previous reports.45 Then we performed a titration of compound 1 over a concentration range within its solubility range (850 μM) (Figure S2B).

While the R2,obs value gradually decreased from 30 to 300 μM of 1, full competition was not observed, suggesting that even though 1 can compete with the reporter molecule, it does not lead to full inhibition of the carbohydrate binding site. This further supports the notion that quinolones bind to a binding site different from the primary carbohydrate site. Next, we tested all the quinolone inhibitors identified here in the 19F RDA to investigate their modulation of the CBS (Figure S2C). Interestingly, the R2,obs value leveled at 4–4.5 s–1 for almost all members of the series, suggesting that none could fully inhibit carbohydrate binding, and since all were selected by a competition assay, all quinolones target the same potential allosteric binding pocket in DC-SIGN. Together, these insights provide a starting point for optimizing the quinolone scaffold to design new allosteric inhibitors of the carbohydrate binding site of DC-SIGN.

In conclusion, we previously identified several secondary binding sites and proposed potential allosteric pockets that would alter the carbohydrate-binding affinity of DC-SIGN.4,30,46 Inspired by highly potent non-carbohydrate inhibitors such as quinoxalinones and oxazolinones,31,32 we constructed a library based on quinolones and identified a series of quinolone-based fragments targeting DC-SIGN. We explored the SAR of these quinolones to identify the influence of substitution on their activity against DC-SIGN. First, we demonstrated that ethoxycarbonyl or dimethylaminocarbonyl in position 2 or 3 is favorable for DC-SIGN binding activity, especially in combination with a substituent in position 7 or 8. Next, we showed that because substituents in position 8 are favorable for DC-SIGN binding activity, position 8 might be interesting for further fragment growing and the introduction of larger substituents. Additionally, 2-aryl-3-hydroxyquinolones did not show activity, suggesting that a phenyl group in position 2 is not favorable for fragment growing, most probably due to steric hindrance. Furthermore, using 19F RDA NMR, we have shown for the first time that quinolones could serve as a starting point for the discovery and optimization of allosteric modulators of the carbohydrate binding site of DC-SIGN. Overall, we believe that our work further supports the notion that targeting allosteric pockets on DC-SIGN is an attractive approach to modulating its carbohydrate binding site. While the affinity of these inhibitors has yet to be improved, quinolones prove to be a valuable starting point for further optimization and development of new DC-SIGN inhibitors.

Acknowledgments

We thank Prof. Dr. Peter H. Seeberger for helpful discussions and the Max Planck Society, University of Chemistry and Technology, Prague and Institute of Organic Chemistry and Biochemistry, Prague for support. H.Z. thanks the China Scholarship Council for a fellowship. K.V. acknowledges the Czech Science Foundation (reg. no. 18-26557Y). Mr. Owen Williams is acknowledged for grammatical correction in this manuscript.

Glossary

Abbreviations

CBS

carbohydrate binding site

CLR

C-type lectin receptor

CRD

carbohydrate recognition domain

CSP

chemical shift perturbation

DC-SIGN

dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin

ECD

extracellular domain

19F RDA NMR

19F reporter displacement NMR assay

LE

ligand efficiency

SAR

structure–activity relationship

STD NMR

1H saturation transfer difference NMR

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.2c00067.

  • Table S1, examples of quinoxalinone inhibitors of DC-SIGN; Table S2, list of the compounds and the characteristics; Figures S1 and S2, 19F NMR data to evaluate the allosteric effect of quinolones; Figures S3–S6, 1H–15N HSQC NMR data to evaluate the affinity of compounds 4, 7, 8, and 9; materials and methods, synthetic procedures, NMR spectra, and additional references (PDF)

Author Contributions

H.Z. characterized SAR by ITC and NMR; D.K. made STD NMR calculation scripts in Python; M.D. characterized compounds’ solubility by NMR; J.Lefèbre offered ideas and corrected the manuscript; O.D., D.M., S.R., and K.V. synthesized the compounds; J.Ledvinka characterized the compounds by NMR and MS; J.H., P.M., and C.R. supervised the work; H.Z., C.R., and P.M. prepared the manuscript.

The authors declare no competing financial interest.

Supplementary Material

ml2c00067_si_001.pdf (5.9MB, pdf)

References

  1. Figdor C. G.; van Kooyk Y.; Adema G. J. C-type lectin receptors on dendritic cells and Langerhans cells. Nat. Rev. Immunol. 2002, 2 (2), 77–84. 10.1038/nri723. [DOI] [PubMed] [Google Scholar]
  2. Ernst B.; Magnani J. L. From carbohydrate leads to glycomimetic drugs. Nat. Rev. Drug Discovery 2009, 8 (8), 661–677. 10.1038/nrd2852. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Williams S. J. Sensing Lipids with Mincle: Structure and Function. Front. Immunol. 2017, 8, 1662. 10.3389/fimmu.2017.01662. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Aretz J.; Anumala U. R.; Fuchsberger F. F.; Molavi N.; Ziebart N.; Zhang H.; Nazare M.; Rademacher C. Allosteric Inhibition of a Mammalian Lectin. J. Am. Chem. Soc. 2018, 140 (44), 14915–14925. 10.1021/jacs.8b08644. [DOI] [PubMed] [Google Scholar]
  5. Jahagirdar P.; Lokhande A. S.; Dandekar P.; Devarajan P. V.. Mannose Receptor and Targeting Strategies. In Targeted Intracellular Drug Delivery by Receptor Mediated Endocytosis; Devarajan P. V., Dandekar P., D’Souza A. A., Eds.; Springer International Publishing: Cham, 2019; pp 433–456. [Google Scholar]
  6. Balzan S.; Lubrano V. LOX-1 receptor: A potential link in atherosclerosis and cancer. Life Sci. 2018, 198, 79–86. 10.1016/j.lfs.2018.02.024. [DOI] [PubMed] [Google Scholar]
  7. Sorensen B.; Mant T.; Akinc A.; Simon A.; Melton L.; Lynam C.; Strahs A.; Sehgal A.; Hutabarat R.; Chaturvedi P.; Barros S.; Vaishnaw A. A Subcutaneously Administered RNAi Therapeutic (ALN-AT3) Targeting Antithrombin for Treatment of Hemophilia: Interim Phase 1 Study Results in Healthy Volunteers and Patients with Hemophilia a or B. Blood 2014, 124 (21), 693. 10.1182/blood.V124.21.693.693. [DOI] [Google Scholar]
  8. Shrimpton R. E.; Butler M.; Morel A. S.; Eren E.; Hue S. S.; Ritter M. A. CD205 (DEC-205): a recognition receptor for apoptotic and necrotic self. Mol. Immunol. 2009, 46 (6), 1229–1239. 10.1016/j.molimm.2008.11.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dhodapkar M. V.; Sznol M.; Zhao B.; Wang D.; Carvajal R. D.; Keohan M. L.; Chuang E.; Sanborn R. E.; Lutzky J.; Powderly J.; Kluger H.; Tejwani S.; Green J.; Ramakrishna V.; Crocker A.; Vitale L.; Yellin M.; Davis T.; Keler T. Induction of Antigen-Specific Immunity with a Vaccine Targeting NY-ESO-1 to the Dendritic Cell Receptor DEC-205. Sci. Transl. Med. 2014, 6 (232), 232ra51. 10.1126/scitranslmed.3008068. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Geurtsen J.; Driessen N. N.; Appelmelk B. J.. Mannose–fucose recognition by DC-SIGN. In Microbial Glycobiology; Holst O., Brennan P. J., Itzstein M. v., Moran A. P., Eds.; Academic Press: San Diego, 2010; Chap. 34, pp 673–695. [Google Scholar]
  11. Geijtenbeek T. B.; Kwon D. S.; Torensma R.; van Vliet S. J.; van Duijnhoven G. C.; Middel J.; Cornelissen I. L.; Nottet H. S.; KewalRamani V. N.; Littman D. R.; Figdor C. G.; van Kooyk Y. DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell 2000, 100 (5), 587–597. 10.1016/S0092-8674(00)80694-7. [DOI] [PubMed] [Google Scholar]
  12. Simmons G.; Reeves J. D.; Grogan C. C.; Vandenberghe L. H.; Baribaud F.; Whitbeck J. C.; Burke E.; Buchmeier M. J.; Soilleux E. J.; Riley J. L.; Doms R. W.; Bates P.; Pöhlmann S. DC-SIGN and DC-SIGNR bind ebola glycoproteins and enhance infection of macrophages and endothelial cells. Virology 2003, 305 (1), 115–123. 10.1006/viro.2002.1730. [DOI] [PubMed] [Google Scholar]
  13. Liu P.; Ridilla M.; Patel P.; Betts L.; Gallichotte E.; Shahidi L.; Thompson N. L.; Jacobson K. Beyond attachment: Roles of DC-SIGN in dengue virus infection. Traffic 2017, 18 (4), 218–231. 10.1111/tra.12469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Amraei R.; Yin W.; Napoleon M. A.; Suder E. L.; Berrigan J.; Zhao Q.; Olejnik J.; Chandler K. B.; Xia C.; Feldman J.; Hauser B. M.; Caradonna T. M.; Schmidt A. G.; Gummuluru S.; Muhlberger E.; Chitalia V.; Costello C. E.; Rahimi N. CD209L/L-SIGN and CD209/DC-SIGN act as receptors for SARS-CoV-2. ACS Cent. Sci. 2021, 7 (7), 1156–1165. 10.1021/acscentsci.0c01537. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Marzi A.; Gramberg T.; Simmons G.; Möller P.; Rennekamp A. J.; Krumbiegel M.; Geier M.; Eisemann J.; Turza N.; Saunier B.; Steinkasserer A.; Becker S.; Bates P.; Hofmann H.; Pohlmann S. DC-SIGN and DC-SIGNR interact with the glycoprotein of Marburg virus and the S protein of severe acute respiratory syndrome coronavirus. J. Virol. 2004, 78 (21), 12090–12095. 10.1128/JVI.78.21.12090-12095.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Han D. P.; Lohani M.; Cho M. W. Specific asparagine-linked glycosylation sites are critical for DC-SIGN- and L-SIGN-mediated severe acute respiratory syndrome coronavirus entry. J. Virol. 2007, 81 (21), 12029–12039. 10.1128/JVI.00315-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Cramer J. Medicinal chemistry of the myeloid C-type lectin receptors Mincle, Langerin, and DC-SIGN. RSC Med. Chem. 2021, 12 (12), 1985–2000. 10.1039/D1MD00238D. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Wen H.-C.; Lin C.-H.; Huang J.-S.; Tsai C.-L.; Chen T.-F.; Wang S.-K. Selective targeting of DC-SIGN by controlling the oligomannose pattern on a polyproline tetra-helix macrocycle scaffold. Chem. Commun. 2019, 55 (62), 9124–9127. 10.1039/C9CC03124C. [DOI] [PubMed] [Google Scholar]
  19. Obermajer N.; Sattin S.; Colombo C.; Bruno M.; Svajger U.; Anderluh M.; Bernardi A. Design, synthesis and activity evaluation of mannose-based DC-SIGN antagonists. Mol. Divers. 2011, 15 (2), 347–360. 10.1007/s11030-010-9285-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Anderluh M.; Jug G.; Svajger U.; Obermajer N. DC-SIGN antagonists, a potential new class of anti-infectives. Curr. Med. Chem. 2012, 19 (7), 992–1007. 10.2174/092986712799320664. [DOI] [PubMed] [Google Scholar]
  21. Varga N.; Sutkeviciute I.; Ribeiro-Viana R.; Berzi A.; Ramdasi R.; Daghetti A.; Vettoretti G.; Amara A.; Clerici M.; Rojo J.; Fieschi F.; Bernardi A. A multivalent inhibitor of the DC-SIGN dependent uptake of HIV-1 and Dengue virus. Biomaterials 2014, 35 (13), 4175–84. 10.1016/j.biomaterials.2014.01.014. [DOI] [PubMed] [Google Scholar]
  22. Tomašić T.; Hajšek D.; Švajger U.; Luzar J.; Obermajer N.; Petit-Haertlein I.; Fieschi F.; Anderluh M. Monovalent mannose-based DC-SIGN antagonists: targeting the hydrophobic groove of the receptor. Eur. J. Med. Chem. 2014, 75, 308–326. 10.1016/j.ejmech.2014.01.047. [DOI] [PubMed] [Google Scholar]
  23. Kotar A.; Tomašič T.; Lenarčič Živković M.; Jug G.; Plavec J.; Anderluh M. STD NMR and molecular modelling insights into interaction of novel mannose-based ligands with DC-SIGN. Org. Biomol. Chem. 2016, 14 (3), 862–875. 10.1039/C5OB01916H. [DOI] [PubMed] [Google Scholar]
  24. Valverde P.; Martínez J. D.; Cañada F. J.; Ardá A.; Jiménez-Barbero J. Molecular Recognition in C-Type Lectins: The Cases of DC-SIGN, Langerin, MGL, and L-Sectin. ChemBioChem. 2020, 21 (21), 2999–3025. 10.1002/cbic.202000238. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Porkolab V.; Chabrol E.; Varga N.; Ordanini S.; Sutkevičiu̅tė I.; Thépaut M.; García-Jiménez M. J.; Girard E.; Nieto P. M.; Bernardi A.; Fieschi F. Rational-Differential Design of Highly Specific Glycomimetic Ligands: Targeting DC-SIGN and Excluding Langerin Recognition. ACS Chem. Biol. 2018, 13 (3), 600–608. 10.1021/acschembio.7b00958. [DOI] [PubMed] [Google Scholar]
  26. Medve L.; Achilli S.; Guzman-Caldentey J.; Thépaut M.; Senaldi L.; Le Roy A.; Sattin S.; Ebel C.; Vivès C.; Martin-Santamaria S.; Bernardi A.; Fieschi F. Enhancing Potency and Selectivity of a DC-SIGN Glycomimetic Ligand by Fragment-Based Design: Structural Basis. Chemistry 2019, 25 (64), 14659–14668. 10.1002/chem.201903391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Cramer J.; Lakkaichi A.; Aliu B.; Jakob R. P.; Klein S.; Cattaneo I.; Jiang X.; Rabbani S.; Schwardt O.; Zimmer G.; Ciancaglini M.; Abreu Mota T.; Maier T.; Ernst B. Sweet Drugs for Bad Bugs: A Glycomimetic Strategy against the DC-SIGN-Mediated Dissemination of SARS-CoV-2. J. Am. Chem. Soc. 2021, 143 (42), 17465–17478. 10.1021/jacs.1c06778. [DOI] [PubMed] [Google Scholar]
  28. Mangold S. L.; Prost L. R.; Kiessling L. L. Quinoxalinone Inhibitors of the Lectin DC-SIGN. Chem. Sci. 2012, 3 (3), 772–777. 10.1039/C2SC00767C. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Schulze J.; Baukmann H.; Wawrzinek R.; Fuchsberger F.; Specker E.; Aretz J.; Nazare M.; Rademacher C. CellFy-A Cell-Based Fragment Screen against C-Type Lectins. ACS Chem. Biol. 2018, 13 (12), 3229–3235. 10.1021/acschembio.8b00875. [DOI] [PubMed] [Google Scholar]
  30. Aretz J.; Baukmann H.; Shanina E.; Hanske J.; Wawrzinek R.; Zapol’skii V. A.; Seeberger P. H.; Kaufmann D. E.; Rademacher C. Identification of Multiple Druggable Secondary Sites by Fragment Screening against DC-SIGN. Angew. Chem., Int. Ed. Engl. 2017, 56 (25), 7292–7296. 10.1002/anie.201701943. [DOI] [PubMed] [Google Scholar]
  31. Borrok M. J.; Kiessling L. L. Non-carbohydrate Inhibitors of the Lectin DC-SIGN. J. Am. Chem. Soc. 2007, 129 (42), 12780–12785. 10.1021/ja072944v. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Mangold S. L.; Prost L. R.; Kiessling L. L. Quinoxalinone inhibitors of the lectin DC-SIGN. Chem. Sci. 2012, 3 (3), 772–777. 10.1039/C2SC00767C. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Keller B. G.; Rademacher C. Allostery in C-type lectins. Curr. Opin. Struct. Biol. 2020, 62, 31–38. 10.1016/j.sbi.2019.11.003. [DOI] [PubMed] [Google Scholar]
  34. Wenthur C. J.; Gentry P. R.; Mathews T. P.; Lindsley C. W. Drugs for allosteric sites on receptors. Annu. Rev. Pharmacol. Toxicol. 2014, 54, 165–184. 10.1146/annurev-pharmtox-010611-134525. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Pham T. D. M.; Ziora Z. M.; Blaskovich M. A. T. Quinolone antibiotics. MedChemComm 2019, 10 (10), 1719–1739. 10.1039/C9MD00120D. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Kathrotiya H. G.; Patel M. P. Synthesis and identification of β-aryloxyquinoline based diversely fluorine substituted N-aryl quinolone derivatives as a new class of antimicrobial, antituberculosis and antioxidant agents. Eur. J. Med. Chem. 2013, 63, 675–684. 10.1016/j.ejmech.2013.03.017. [DOI] [PubMed] [Google Scholar]
  37. Biagini G. A.; Fisher N.; Shone A. E.; Mubaraki M. A.; Srivastava A.; Hill A.; Antoine T.; Warman A. J.; Davies J.; Pidathala C.; Amewu R. K.; Leung S. C.; Sharma R.; Gibbons P.; Hong D. W.; Pacorel B.; Lawrenson A. S.; Charoensutthivarakul S.; Taylor L.; Berger O.; Mbekeani A.; Stocks P. A.; Nixon G. L.; Chadwick J.; Hemingway J.; Delves M. J.; Sinden R. E.; Zeeman A.-M.; Kocken C. H. M.; Berry N. G.; O’Neill P. M.; Ward S. A. Generation of quinolone antimalarials targeting the Plasmodium falciparum mitochondrial respiratory chain for the treatment and prophylaxis of malaria. Proc. Natl. Acad. Sci. U.S.A. 2012, 109 (21), 8298–8303. 10.1073/pnas.1205651109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Kumar D. V.; Rai R.; Brameld K. A.; Somoza J. R.; Rajagopalan R.; Janc J. W.; Xia Y. M.; Ton T. L.; Shaghafi M. B.; Hu H.; Lehoux I.; To N.; Young W. B.; Green M. J. Quinolones as HCV NS5B polymerase inhibitors. Bioorg. Med. Chem. Lett. 2011, 21 (1), 82–87. 10.1016/j.bmcl.2010.11.068. [DOI] [PubMed] [Google Scholar]
  39. Wang R.; Xu K.; Shi W. Quinolone derivatives: Potential anti-HIV agent-development and application. Arch. Pharm. Chem. Life Sci. 2019, 352 (9), e1900045. 10.1002/ardp.201900045. [DOI] [PubMed] [Google Scholar]
  40. Yadav V.; Talwar P. Repositioning of fluoroquinolones from antibiotic to anti-cancer agents: An underestimated truth. Biomed. Pharmacother. 2019, 111, 934–946. 10.1016/j.biopha.2018.12.119. [DOI] [PubMed] [Google Scholar]
  41. Edmont D.; Rocher R.; Plisson C.; Chenault J. Synthesis and evaluation of quinoline carboxyguanidines as antidiabetic agents. Med. Chem. Lett. 2000, 10 (16), 1831–1834. 10.1016/S0960-894X(00)00354-1. [DOI] [PubMed] [Google Scholar]
  42. Cala O.; Krimm I. Ligand-Orientation Based Fragment Selection in STD NMR Screening. Eur. J. Med. Chem. 2015, 58 (21), 8739–8742. 10.1021/acs.jmedchem.5b01114. [DOI] [PubMed] [Google Scholar]
  43. Wang Y. S.; Liu D.; Wyss D. F. Competition STD NMR for the detection of high-affinity ligands and NMR-based screening. Magn. Reson. Chem. 2004, 42 (6), 485–489. 10.1002/mrc.1381. [DOI] [PubMed] [Google Scholar]
  44. Wamhoff E.-C.; Hanske J.; Schnirch L.; Aretz J.; Grube M.; Varón Silva D.; Rademacher C. 19F NMR-Guided Design of Glycomimetic Langerin Ligands. ACS Chem. Biol. 2016, 11 (9), 2407–2413. 10.1021/acschembio.6b00561. [DOI] [PubMed] [Google Scholar]
  45. Wawrzinek R.; Wamhoff E. C.; Lefebre J.; Rentzsch M.; Bachem G.; Domeniconi G.; Schulze J.; Fuchsberger F. F.; Zhang H.; Modenutti C.; Schnirch L.; Marti M. A.; Schwardt O.; Bräutigam M.; Guberman M.; Hauck D.; Seeberger P. H.; Seitz O.; Titz A.; Ernst B.; Rademacher C. A Remote Secondary Binding Pocket Promotes Heteromultivalent Targeting of DC-SIGN. J. Am. Chem. Soc. 2021, 143 (45), 18977–18988. 10.1021/jacs.1c07235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Hanske J.; Aleksić S.; Ballaschk M.; Jurk M.; Shanina E.; Beerbaum M.; Schmieder P.; Keller B. G.; Rademacher C. Intradomain Allosteric Network Modulates Calcium Affinity of the C-Type Lectin Receptor Langerin. J. Am. Chem. Soc. 2016, 138 (37), 12176–12186. 10.1021/jacs.6b05458. [DOI] [PubMed] [Google Scholar]
  47. Hopkins A. L.; Groom C. R.; Alex A. Ligand efficiency: a useful metric for lead selection. Drug Discovery Today 2004, 9 (10), 430–431. 10.1016/S1359-6446(04)03069-7. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ml2c00067_si_001.pdf (5.9MB, pdf)

Articles from ACS Medicinal Chemistry Letters are provided here courtesy of American Chemical Society

RESOURCES