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1.
Biochemistry ; 62(7): 1321-1329, 2023 04 04.
Artículo en Inglés | MEDLINE | ID: mdl-36883372

RESUMEN

The Myb transcription factor is involved in the proliferation of hematopoietic cells, and deregulation of its expression can lead to cancers such as leukemia. Myb interacts with various proteins, including the histone acetyltransferases p300 and CBP. Myb binds to a small domain of p300, the KIX domain (p300KIX), and inhibiting this interaction is a potential new drug discovery strategy in oncology. The available structures show that Myb binds to a very shallow pocket of the KIX domain, indicating that it might be challenging to identify inhibitors of this interaction. Here, we report the design of Myb-derived peptides which interact with p300KIX. We show that by mutating only two Myb residues that bind in or near a hotspot at the surface of p300KIX, it is possible to obtain single-digit nanomolar peptidic inhibitors of the Myb/p300KIX interaction that bind 400-fold tighter to p300KIX than wildtype Myb. These findings suggest that it might also be possible to design potent low molecular-weight compounds to disrupt the Myb/p300KIX interaction.


Asunto(s)
Proteína p300 Asociada a E1A , Péptidos , Proteínas Proto-Oncogénicas c-myb , Péptidos/farmacología , Unión Proteica , Proteínas Proto-Oncogénicas c-myb/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-myb/química , Proteína p300 Asociada a E1A/antagonistas & inhibidores , Proteína p300 Asociada a E1A/química
2.
Bioorg Med Chem Lett ; 25(3): 438-43, 2015 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-25571794

RESUMEN

Adenoviral infections are associated with a wide range of acute diseases, among which ocular viral conjunctivitis (EKC) and disseminated disease in immunocompromised patients. To date, no approved specific anti-adenoviral drug is available, but there is a growing need for an effective treatment of such infections. The adenoviral protease, adenain, plays a crucial role for the viral lifecycle and thus represents an attractive therapeutic target. Structure-guided design with the objective to depeptidize tetrapeptide nitrile 1 led to the novel chemotype 2. Optimization of scaffold 2 resulted in picomolar adenain inhibitors 3a and 3b. In addition, a complementary series of irreversible vinyl sulfone containing inhibitors were rationally designed, prepared and evaluated against adenoviral protease. High resolution X-ray co-crystal structures of representatives of each series proves the successful design of these inhibitors and provides an excellent basis for future medicinal chemistry optimization of these compounds.


Asunto(s)
Adenoviridae/enzimología , Antivirales/química , Cisteína Endopeptidasas/química , Diseño de Fármacos , Inhibidores de Proteasas/química , Proteínas Virales/antagonistas & inhibidores , Adenoviridae/efectos de los fármacos , Antivirales/metabolismo , Antivirales/toxicidad , Sitios de Unión , Cristalografía por Rayos X , Cisteína Endopeptidasas/metabolismo , Células HEK293 , Humanos , Simulación del Acoplamiento Molecular , Inhibidores de Proteasas/metabolismo , Inhibidores de Proteasas/toxicidad , Unión Proteica , Estructura Terciaria de Proteína , Relación Estructura-Actividad , Proteínas Virales/metabolismo
3.
Cell Chem Biol ; 29(2): 249-258.e5, 2022 02 17.
Artículo en Inglés | MEDLINE | ID: mdl-34547225

RESUMEN

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates plasma low-density lipoprotein cholesterol (LDL-C) levels by promoting hepatic LDL receptor (LDLR) degradation. Therapeutic antibodies that disrupt PCSK9-LDLR binding reduce LDL-C concentrations and cardiovascular disease risk. The epidermal growth factor precursor homology domain A (EGF-A) of the LDLR serves as a primary contact with PCSK9 via a flat interface, presenting a challenge for identifying small molecule PCSK9-LDLR disruptors. We employ an affinity-based screen of 1013in vitro-translated macrocyclic peptides to identify high-affinity PCSK9 ligands that utilize a unique, induced-fit pocket and partially disrupt the PCSK9-LDLR interaction. Structure-based design led to molecules with enhanced function and pharmacokinetic properties (e.g., 13PCSK9i). In mice, 13PCSK9i reduces plasma cholesterol levels and increases hepatic LDLR density in a dose-dependent manner. 13PCSK9i functions by a unique, allosteric mechanism and is the smallest molecule identified to date with in vivo PCSK9-LDLR disruptor function.


Asunto(s)
Péptidos/farmacología , Proproteína Convertasa 9/metabolismo , Receptores de LDL/antagonistas & inhibidores , Animales , Relación Dosis-Respuesta a Droga , Células Hep G2 , Humanos , Ligandos , Masculino , Ratones , Ratones Endogámicos C57BL , Péptidos/síntesis química , Péptidos/química , Conformación Proteica , Receptores de LDL/metabolismo
4.
Angew Chem Int Ed Engl ; 40(2): 381-385, 2001 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-29712393

RESUMEN

Solid-supported diazoalkane analogues for the smooth and clean esterifications of carboxylic acids [Eq. (1)] as well as of complex compound mixtures: the alkylating polymers presented here were synthesized as solid-supported 3-alkyl-1-aryltriazenes and are capable of releasing carbenium ions following acidic activation.

5.
ACS Med Chem Lett ; 5(8): 937-41, 2014 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-25147618

RESUMEN

The cysteine protease adenain is the essential protease of adenovirus and, as such, represents a promising target for the treatment of ocular and other adenoviral infections. Through a concise two-pronged hit discovery approach we identified tetrapeptide nitrile 1 and pyrimidine nitrile 2 as complementary starting points for adenain inhibition. These hits enabled the first high-resolution X-ray cocrystal structures of adenain with inhibitors bound and revealed the binding mode of 1 and 2. The screening hits were optimized by a structure-guided medicinal chemistry strategy into low nanomolar drug-like inhibitors of adenain.

6.
ACS Med Chem Lett ; 5(7): 787-92, 2014 Jul 10.
Artículo en Inglés | MEDLINE | ID: mdl-25050166

RESUMEN

A cis-configured 3,5-disubstituted piperidine direct renin inhibitor, (syn,rac)-1, was discovered as a high-throughput screening hit from a target-family tailored library. Optimization of both the prime and the nonprime site residues flanking the central piperidine transition-state surrogate resulted in analogues with improved potency and pharmacokinetic (PK) properties, culminating in the identification of the 4-hydroxy-3,5-substituted piperidine 31. This compound showed high in vitro potency toward human renin with excellent off-target selectivity, 60% oral bioavailability in rat, and dose-dependent blood pressure lowering effects in the double-transgenic rat model.

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