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1.
ACS Infect Dis ; 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38905481

RESUMO

Fungi pose a global threat to humankind due to the increasing emergence of multi-drug-resistant fungi. There is a rising incidence of invasive fungal infections. Due to the structural complexity of fungal cell membranes, only a few classes of antifungal agents are effective and have been approved by the U.S. FDA. Hence, researchers globally are focusing on developing novel strategies to cure fungal infections. One of the potential strategies is the "Trojan horse" approach, which uses the siderophore-mediated iron acquisition (SIA) system to scavenge iron to deliver potent antifungal agents for therapeutics and diagnostics. These siderophore conjugates chelate to iron and are taken up through siderophore-iron transporters, which are overexpressed exclusively on microbes such as bacteria or fungi, but not mammalian cells. Our comprehensive review delves into recent advancements in the design of siderophore-conjugated antifungal agents to gain fungal cell entry. Notably, our focus extends to unraveling the intricate relationship between the structure of natural siderophores or siderophore-like molecules and the resulting antifungal activity. By exploring these design strategies, we aim to contribute to the ongoing discourse on combating drug-resistant fungal infections and advancing the landscape of antifungal theranostics.

2.
Angew Chem Int Ed Engl ; 62(24): e202219095, 2023 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-37067463

RESUMO

RAS proteins control various intracellular signaling networks. Mutations at specific locations were shown to stabilize their active guanosine triphosphate (GTP)-bound state, which is associated with the development of multiple cancers. An attractive approach to modulate RAS signaling is through its regulatory guanine nucleotide exchange factor (GEF) son of sevenless 1 (SOS1). With the recent discovery of Nanobody14 (Nb14), which potently enhances SOS1-catalyzed nucleotide exchange on RAS, we explored the feasibility of developing peptide mimetics by structurally mimicking the complementarity-determining region 3 (CDR3). Guided by a biochemical GEF assay and X-ray co-crystal structures, successive rounds of optimization and gradual conformational rigidification led to CDR3 mimetics showing half of the maximal activation potential of Nb14 with an EC50 value of 29 µM. Altogether, this study demonstrated that peptides able to modulate a protein-protein interaction can be obtained by structural mimicry of a Nb paratope.


Assuntos
Núcleo Familiar , Nucleotídeos , Transdução de Sinais , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Catálise
3.
Beilstein J Org Chem ; 19: 245-281, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36895430

RESUMO

Terpene compounds probably represent the most diversified class of secondary metabolites. Some classes of terpenes, mainly diterpenes (C20) and sesterterpenes (C25) and to a lesser extent sesquiterpenes (C15), share a common bicyclo[3.6.0]undecane core which is characterized by the presence of a cyclooctane ring fused to a cyclopentane ring, i.e., a [5-8] bicyclic ring system. This review focuses on the different strategies elaborated to construct this [5-8] bicyclic ring system and their application in the total synthesis of terpenes over the last two decades. The overall approaches involve the construction of the 8-membered ring from an appropriate cyclopentane precursor. The proposed strategies include metathesis, Nozaki-Hiyama-Kishi (NHK) cyclization, Pd-mediated cyclization, radical cyclization, Pauson-Khand reaction, Lewis acid-promoted cyclization, rearrangement, cycloaddition and biocatalysis.

4.
Molecules ; 26(17)2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34500841

RESUMO

Opioid agonists are well-established analgesics, widely prescribed for acute but also chronic pain. However, their efficiency comes with the price of drastically impacting side effects that are inherently linked to their prolonged use. To answer these liabilities, designed multiple ligands (DMLs) offer a promising strategy by co-targeting opioid and non-opioid signaling pathways involved in nociception. Despite being intimately linked to the Substance P (SP)/neurokinin 1 (NK1) system, which is broadly examined for pain treatment, the neurokinin receptors NK2 and NK3 have so far been neglected in such DMLs. Herein, a series of newly designed opioid agonist-NK2 or -NK3 antagonists is reported. A selection of reported peptidic, pseudo-peptidic, and non-peptide neurokinin NK2 and NK3 ligands were covalently linked to the peptidic µ-opioid selective pharmacophore Dmt-DALDA (H-Dmt-d-Arg-Phe-Lys-NH2) and the dual µ/δ opioid agonist H-Dmt-d-Arg-Aba-ßAla-NH2 (KGOP01). Opioid binding assays unequivocally demonstrated that only hybrids SBL-OPNK-5, SBL-OPNK-7 and SBL-OPNK-9, bearing the KGOP01 scaffold, conserved nanomolar range µ-opioid receptor (MOR) affinity, and slightly reduced affinity for the δ-opioid receptor (DOR). Moreover, NK binding experiments proved that compounds SBL-OPNK-5, SBL-OPNK-7, and SBL-OPNK-9 exhibited (sub)nanomolar binding affinity for NK2 and NK3, opening promising opportunities for the design of next-generation opioid hybrids.


Assuntos
Analgésicos Opioides/química , Antagonistas dos Receptores de Neurocinina-1/química , Peptidomiméticos/química , Receptores da Neurocinina-1/química , Receptores Opioides mu/química , Sequência de Aminoácidos , Humanos , Ligantes , Oligopeptídeos/química , Ligação Proteica , Conformação Proteica , Relação Estrutura-Atividade , Substância P/química
5.
Org Biomol Chem ; 19(31): 6771-6775, 2021 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-34292288

RESUMO

Enantiopure α-Tfm-proline and α-Tfm-pipecolic acid were synthesized starting from commercially available diesters and ethyl trifluoroacetate. A Strecker type reaction on intermediate chiral Tfm-oxazolo-pyrrolidine and -piperidine provided the corresponding nitrile precursor of enantiopure (R) and (S) α-Tfm-proline and α-Tfm-pipecolic acid. The C-terminal peptide coupling reaction of α-Tfm-pipecolic acid has been successfully achieved.

6.
Org Lett ; 23(2): 382-387, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33369434

RESUMO

The straightforward synthesis of enantiopure 5-(R)-and 5-(S)-trifluoromethylproline is reported. The key steps are a Ruppert-Prakash reagent addition on l-pyroglutamic esters followed by an elimination reaction and a selective reduction. The solution-phase and solid-phase incorporation of this unprotected enantiopure fluorinated amino acid in a short peptide chain was demonstrated. Compared to proline, the CF3 group provides a decrease of the trans to cis amide bond isomerization energy and an increase of the cis conformer population.


Assuntos
Amidas/química , Aminoácidos/química , Peptídeos/química , Prolina/química , Indicadores e Reagentes/química , Isomerismo , Estrutura Molecular
7.
Curr Med Chem ; 27(9): 1515-1561, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30209994

RESUMO

The neurokinins are indisputably essential neurotransmitters in numerous pathoand physiological events. Being widely distributed in the Central Nervous System (CNS) and peripheral tissues, their discovery rapidly promoted them to drugs targets. As a necessity for molecular tools to understand the biological role of this class, endogenous peptides and their receptors prompted the scientific community to design ligands displaying either agonist and antagonist activity at the three main neurokinin receptors, called NK1, NK2 and NK3. Several strategies were implemented for this purpose. With a preference to small non-peptidic ligands, many research groups invested efforts in synthesizing and evaluating a wide range of scaffolds, but only the NK1 antagonist Aprepitant (EMENDT) and its prodrug Fosaprepitant (IVEMENDT) have been approved by the Food Drug Administration (FDA) for the treatment of Chemotherapy-Induced and Post-Operative Nausea and Vomiting (CINV and PONV, respectively). While non-peptidic drugs showed limitations, especially in side effect control, peptidic and pseudopeptidic compounds progressively regained attention. Various strategies were implemented to modulate affinity, selectivity and activity of the newly designed ligands. Replacement of canonical amino acids, incorporation of conformational constraints, and fusion with non-peptidic moieties gave rise to families of ligands displaying individual or dual NK1, NK2 and NK3 antagonism, that ultimately were combined with non-neurokinin ligands (such as opioids) to target enhanced biological impact.


Assuntos
Peptidomiméticos/farmacologia , Humanos , Ligantes , Antagonistas dos Receptores de Neurocinina-1 , Receptores da Neurocinina-1 , Vômito
8.
Chembiochem ; 20(19): 2513-2518, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31062451

RESUMO

Proline is often found as a turn inducer in peptide or protein domains. Exploitation of its restricted conformational freedom led to the development of the d-Pro-l-Pro (corresponding to (R)-Pro-(S)-Pro) segment as a "templating" unit, frequently used in the design of ß-hairpin peptidomimetics, in which conformational stability is, however, inherently linked to the cis-trans isomerization of the prolyl amide bonds. In this context, the stereoelectronic properties of the CF3 group can aid in conformational control. Herein, the impact of α-trifluoromethylated proline analogues is examined for the design of enhanced ß-turn inducers. A theoretical conformational study permitted the dipeptide (R)-Pro-(R)-TfmOxa (TfmOxa: 2-trifluoromethyloxazolidine-2-carboxylic acid) to be selected as a template with an increased trans-cis rotational energy barrier. NMR spectroscopic analysis of the Ac-(R)-Pro-(R)-TfmOxa-(S)-Val-OtBu ß-turn model, obtained through an original synthetic pathway, validated the prevalence of a major trans-trans conformer and indicated the presence of an internal hydrogen bond. Altogether, it was shown that the (R)-Pro-(R)-TfmOxa template fulfilled all crucial ß-turn-inducer criteria.


Assuntos
Ácidos Carboxílicos/química , Dipeptídeos/química , Oxazolona/análogos & derivados , Prolina/análogos & derivados , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética , Metilação , Oxazolona/química , Conformação Proteica , Termodinâmica
9.
Chembiochem ; 19(10): 1026-1030, 2018 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-29513394

RESUMO

In order to achieve accurate determination of the local hydrophobicity increases in peptide sequences produced by incorporation of trifluoromethylated amino acids (TfmAAs), the chromatographic hydrophobicity indexes (ϕ0 ) of three series of tripeptides containing three unnatural trifluoromethylated amino acids have been measured and compared with those of their non-fluorinated analogues. The hydrophobic contribution of each fluorinated amino acid was quantified by varying the position and the protection of (R)- and (S)-α-trifluoromethylalanine (TfmAla), (R)-trifluoromethylcysteine (TfmCys), and (S)-trifluoromethionine (TFM) in a short peptide sequence. As a general trend, strong increases in hydrophobicity were precisely measured, even exceeding the high hydrophobic contribution of the natural amino acid isoleucine. This study validates the incorporation of trifluoromethylated amino acids into peptide sequences as a rational strategy for the fine-tuning of hydrophobic peptide-protein interactions.


Assuntos
Alanina/análogos & derivados , Cisteína/química , Metionina/análogos & derivados , Peptídeos/química , Alanina/química , Sequência de Aminoácidos , Cisteína/análise , Halogenação , Interações Hidrofóbicas e Hidrofílicas , Metionina/química
10.
RSC Adv ; 8(26): 14597-14602, 2018 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-35540789

RESUMO

The synthesis of four CF3-proline analogues of the PLG peptide is reported. Our results show that the incorporation of trifluoromethylated amino acids (Tfm-AAs) at the N-terminal position of a peptide significantly increases its hydrophobicity. In addition, depending on the relative configuration and the position of the CF3 group, Tfm-AAs can also promote passive diffusion transport.

11.
Bioorg Med Chem Lett ; 24(12): 2724-7, 2014 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-24815511

RESUMO

A series of 5-aryl-2-(3-thienylamino)-1,3,4-thiadiazoles 3a-m were synthesized in good yields in two steps starting from thiophen-3-isothiocyanates. Those compounds as well as the thiosemicarbazide intermediates 2a-m were screened for their antiproliferative activity against a panel of six cancer cell lines. Among them, two 5-aryl-2-(3-thienylamino)-1,3,4-thiadiazoles (3f and 3i) have shown very interesting results with IC50 <10µM on three cell lines.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Tiadiazóis/síntese química , Tiadiazóis/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Tiadiazóis/química
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