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1.
J Med Chem ; 64(12): 8010-8041, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34107682

RESUMO

Toll-like receptors (TLRs) are members of a large family of evolutionarily conserved pattern recognition receptors (PRRs), which serve as key components of the innate immune system by playing a pivotal role in sensing "nonself" ligands. Endosomal TLRs (TLR3, TLR7, TLR8, and TLR9) can recognize pathogen-derived nucleic acid and initiate an innate immune response because they react against both self- and non-self-origin nucleic acid molecules. Accordingly, both receptor agonists and antagonists are potentially useful in disparate clinical contexts and thus are globally sought after. Recent research has revealed that agonists and antagonists share an overlapping binding region. This Perspective highlights rational medicinal chemistry approaches to elucidate the structural attributes of small molecules capable of agonism or antagonism or of elegantly switching between the two. The structural evolution of different chemotypes can provide the framework for the future development of endosomal TLR agonists and antagonists.


Assuntos
Compostos Heterocíclicos/química , Receptores Toll-Like/agonistas , Receptores Toll-Like/antagonistas & inibidores , Animais , Endossomos/química , Células HEK293 , Compostos Heterocíclicos/metabolismo , Compostos Heterocíclicos/farmacologia , Humanos , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Receptores Toll-Like/metabolismo
2.
J Med Chem ; 64(13): 9279-9301, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34142551

RESUMO

Several toll-like receptors (TLRs) reside inside endosomes of specific immune cells-among them, aberrant activation of TLR7 and TLR9 is implicated in myriad contexts of autoimmune diseases, making them promising therapeutic targets. However, small-molecule TLR7 and TLR9 antagonists are not yet available for clinical use. We illustrate here the importance of C2, C6, and N9 substitutions in the purine scaffold for antagonism to TLR7 and TLR9 through structure-activity relationship studies using cellular reporter assays and functional studies on primary human immune cells. Further in vitro and in vivo pharmacokinetic studies identified an orally bioavailable lead compound 29, with IC50 values of 0.08 and 2.66 µM against TLR9 and TLR7, respectively. Isothermal titration calorimetry excluded direct TLR ligand-antagonist interactions. In vivo antagonism efficacy against mouse TLR9 and therapeutic efficacy in a preclinical murine model of psoriasis highlighted the potential of compound 29 as a therapeutic candidate in relevant autoimmune contexts.


Assuntos
Purinas/farmacologia , Receptor 7 Toll-Like/antagonistas & inibidores , Receptor Toll-Like 9/antagonistas & inibidores , Administração Oral , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Purinas/administração & dosagem , Purinas/química , Ratos , Relação Estrutura-Atividade
3.
Biochimie ; 183: 100-107, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33476699

RESUMO

The folate and methionine cycles, constituting one-carbon metabolism, are critical pathways for cell survival. Intersecting these two cycles, 5,10-methylenetetrahydrofolate reductase (MTHFR) directs one-carbon units from the folate to methionine cycle, to be exclusively used for methionine and S-adenosylmethionine (AdoMet) synthesis. MTHFR deficiency and upregulation result in diverse disease states, rendering it an attractive drug target. The activity of MTHFR is inhibited by the binding of AdoMet to an allosteric regulatory domain distal to the enzyme's active site, which we have previously identified to constitute a novel fold with a druggable pocket. Here, we screened 162 AdoMet mimetics using differential scanning fluorimetry, and identified 4 compounds that stabilized this regulatory domain. Three compounds were sinefungin analogues, closely related to AdoMet and S-adenosylhomocysteine (AdoHcy). The strongest thermal stabilisation was provided by (S)-SKI-72, a potent inhibitor originally developed for protein arginine methyltransferase 4 (PRMT4). Using surface plasmon resonance, we confirmed that (S)-SKI-72 binds MTHFR via its allosteric domain with nanomolar affinity. Assay of MTHFR activity in the presence of (S)-SKI-72 demonstrates inhibition of purified enzyme with sub-micromolar potency and endogenous MTHFR from HEK293 cell lysate in the low micromolar range, both of which are lower than AdoMet. Nevertheless, unlike AdoMet, (S)-SKI-72 is unable to completely abolish MTHFR activity, even at very high concentrations. Combining binding assays, kinetic characterization and compound docking, this work indicates the regulatory domain of MTHFR can be targeted by small molecules and presents (S)-SKI-72 as an excellent candidate for development of MTHFR inhibitors.


Assuntos
Inibidores Enzimáticos/química , Metilenotetra-Hidrofolato Redutase (NADPH2)/antagonistas & inibidores , Metilenotetra-Hidrofolato Redutase (NADPH2)/química , S-Adenosilmetionina/química , Regulação Alostérica , Humanos , Domínios Proteicos
4.
Eur J Med Chem ; 210: 112978, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33189437

RESUMO

Aberrant activation of the endosomal Toll-like receptor 7 (TLR7) has been implicated in myriad autoimmune diseases and is an established therapeutic target in such conditions. Development of diverse TLR7 antagonists is mainly accomplished through random screening. To correlate human TLR7 (hTLR7) antagonistic activity with the structural features in different chemotypes, we derived a hypothetical binding model based on molecular docking analysis along with molecular dynamics (MD) simulations study. The binding hypothesis revealed different pockets, grooves and a central cavity where ligand-receptor interaction with specific residues through hydrophobic and hydrogen bond interactions take place, which correlate with TLR7 antagonistic activity thus paving the way for rational design using varied chemotypes. Based on the structural insight thus gained, TLR7 antagonists with quinazoline were designed to understand the effect of engagement of these pockets as well as boundaries of the chemical space associated with them. The newly synthesized most potent hTLR7 antagonist, i.e. compound 63, showed IC50 value of 1.03 ± 0.05 µM and was validated by performing primary assay in human plasmacytoid dendritic cells (pDC) (IC50pDC: 1.42 µM). The biological validation of the synthesized molecules was performed in TLR7-reporter HEK293 cells as well as in human plasmacytoid dendritic cells (pDCs). Our study provides a rational design approach thus facilitating further development of novel small molecule hTLR7 antagonists based on different chemical scaffolds.


Assuntos
Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Quinazolinas/farmacologia , Receptor 7 Toll-Like/antagonistas & inibidores , Sítios de Ligação/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Estrutura Molecular , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade , Receptor 7 Toll-Like/metabolismo
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