877754-71-7

Upstream product

• 1464-43-3 seleno-L-cystine 
• 24424-99-5 di-tert-butyl dicarbonate 
• 143966-57-8 (S)-allyl 2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoate 
• 3262-72-4 (S)-N-(tert-butoxycarbonyl)serine 
• 93267-04-0 N-(tert-butoxycarbonyl)-L-3-iodoalanine methyl ester 
• 56926-94-4 methyl (2S)-2-[N-(t-butoxycarbonyl)amino]-3-(4-methylbenzenesulfonyl)-oxypropionate 
• 2766-43-0 N-tert-butyloxycarbonyl-L-serine methyl ester 
• 195324-31-3 dimethyl 3,3'-diselanediyl-(2R,2'R)-bis(2-((tertbutoxycarbonyl)amino)propanoate) 

Downstream Products

• 959415-39-5 (R)-2-((tert-butoxycarbonyl)amino)-3-((4-methoxybenzyl)selanyl)propanoic acid 
• 869646-27-5 N-Boc-L-Sec(4-MeBzl)-OH 

Relevant academic research and scientific papers

Site-Specific Incorporation of Selenocysteine Using an Expanded Genetic Code and Palladium-Mediated Chemical Deprotection

Selenoproteins containing the 21st amino acid selenocysteine (Sec) exist in all three kingdoms of life and play essential roles in human health and development. The distinct low pKa, high reactivity, and redox property of Sec also afford unique routes to protein modification and engineering. However, natural Sec incorporation requires idiosyncratic translational machineries that are dedicated to Sec and species-dependent, which makes it challenging to recombinantly prepare selenoproteins with high Sec specificity. As a consequence, the function of half of human selenoproteins remains unclear, and Sec-based protein manipulation has been greatly hampered. Here we report a new general method enabling the site-specific incorporation of Sec into proteins in E. coli. An orthogonal tRNAPyl-ASecRS was evolved to specifically incorporate Se-allyl selenocysteine (ASec) in response to the amber codon, and the incorporated ASec was converted to Sec in high efficiency through palladium-mediated cleavage under mild conditions compatible with proteins and cells. This approach completely obviates the natural Sec-dedicated factors, thus allowing various selenoproteins, regardless of Sec position and species source, to be prepared with high Sec specificity and enzyme activity, as shown by the preparation of human thioredoxin and glutathione peroxidase 1. Sec-selective labeling in the presence of Cys was also demonstrated on the surface of live E. coli cells. The tRNAPyl-ASecRS pair was further used in mammalian cells to incorporate ASec, which was converted into Sec by palladium catalyst in cellulo. This robust and versatile method should greatly facilitate the study of diverse natural selenoproteins and the engineering of proteins in general via site-specific introduction of Sec.

DEPALMITOYLATING COMPOSITIONS AND THE USE THEREOF

Disclosed herein, inter alia, are depalmitoylating compounds, compositions, and methods of use thereof.

Chemical and Ribosomal Synthesis of Topologically Controlled Bicyclic and Tricyclic Peptide Scaffolds Primed by Selenoether Formation

Bicyclic and tricyclic peptides have emerged as promising candidates for the development of protein binders and new therapeutics. However, convenient and efficient strategies that can generate topologically controlled bicyclic and tricyclic peptide scaffolds from fully-unprotected peptides are still much in demand, particularly for those amenable to the design of biosynthetic libraries. In this work, we report a reliable chemical and ribosomal synthesis of topologically controlled bicyclic and tricyclic peptide scaffolds. Our strategy involves the combination of selenoether cyclization followed by disulfide or thioether cyclization, yielding desirable bicyclic and tricyclic peptides. This work thus lays the foundation for developing peptide libraries with controlled topology of multicyclic scaffolds for in vitro display techniques.

Elongation of the Hydrophobic Chain as a Molecular Switch: Discovery of Capsaicin Derivatives and Endogenous Lipids as Potent Transient Receptor Potential Vanilloid Channel 2 Antagonists

The transient receptor potential vanilloid type-2 (TRPV2) protein is a nonselective Ca2+ permeable channel member of the TRPV subfamily, still considered an orphan TRP channel due to the scarcity of available selective and potent pharmacological tools and endogenous modulators. Here we describe the discovery of novel synthetic long-chain capsaicin derivatives as potent TRPV2 antagonists in comparison to the totally inactive capsaicin, the role of their hydrophobic chain, and how the structure-activity relationships of such derivatives led, through a ligand-based approach, to the identification of endogenous long-chain fatty acid ethanolamides or primary amides acting as TRPV2 antagonists. Both synthetic and endogenous antagonists exhibited differential inhibition against known TRPV2 agonists characterized by distinct kinetic profiles. These findings represent the first example of both synthetic and naturally occurring TRPV2 modulators with efficacy in the submicromolar/low-micromolar range, which will be useful for clarifying the physiopathological roles of this receptor, its regulation, and its targeting in pathological conditions.

Chemoselective modifications for the traceless ligation of thioamide-containing peptides and proteins

Thioamides are single-atom substitutions of canonical amide bonds, and have been proven to be versatile and minimally perturbing probes in protein folding studies. Previously, our group showed that thioamides can be incorporated into proteins by native chemical ligation (NCL) with Cys as a ligation handle. In this study, we report the expansion of this strategy into non-Cys ligation sites, utilizing radical initiated desulfurization to "erase" the side chain thiol after ligation. The reaction exhibited high chemoselectivity against thioamides, which can be further enhanced with thioacetamide as a sacrificial scavenger. As a proof-of-concept example, we demonstrated the incorporation of a thioamide probe into a 56 amino acid protein, the B1 domain of Protein G (GB1). Finally, we showed that the method can be extended to β-thiol amino acid analogs and selenocysteine.

Assessment of reagents for selenocysteine conjugation and the stability of selenocysteine adducts

Conventional antibody-drug conjugates (ADCs) are heterogeneous mixtures that have poor pharmacokinetic properties and decreased efficacy relative to homogenous ADCs. Furthermore, ADCs that are maleimide-based often have inadequate circulatory stability, which can result in premature drug release with consequent off-target toxicities. Selenocysteine-modified antibodies have been developed that allow site-specific antibody conjugation, yielding homogeneous ADCs. Herein, we survey several electrophilic functional groups that react with selenocystine with high efficiency. Several of these result in conjugates with stabilities that are superior to maleimide conjugates. Among these, the allenamide functional group reacts with notably high efficiency, leads to conjugates with remarkable stability, and shows exquisite selectivity for selenocysteine conjugation.

Biosynthetic selenoproteins with genetically-encoded photocaged selenocysteines

Selenocysteine is a valuable component of both natural selenoproteins and designer biocatalysts; however the availability of such proteins is hampered by technical limitations. Here we report the first general strategy for the production of selenoproteins via genetically-encoded incorporation of a synthetic photocaged selenocysteine residue in yeast cells, and provide examples of light-controlled protein dimerization and targeted covalent labeling in vitro.

Oxidative deselenization of selenocysteine: Applications for programmed ligation at serine

Despite the unique chemical properties of selenocysteine (Sec), ligation at Sec is an under-utilized methodology for protein synthesis. We describe herein an unprecedented protocol for the conversion of Sec to serine (Ser) in a single, high-yielding step.

A comprehensive one-pot synthesis of protected cysteine and selenocysteine SPPS derivatives

A proof-of-principle methodology is presented in which all commercially-available cysteine (Cys) and selenocysteine (Sec) solid phase peptide synthesis (SPPS) derivatives are synthesized in high yield from easily prepared protected dichalcogenide precursors. A Zn-mediated biphasic reduction process applied to a series of four bis-Nα-protected dichalcogenide compounds allows facile conversion to their corresponding thiol and selenol intermediates followed by insitu S- or Se-alkylation with various electrophiles to directly access twenty one known Cys and Sec SPPS derivatives. Most of these derivatives were able to be precipitated in crude form out of petroleum ether in sufficient purity for direct use as peptide building blocks. Subsequent incorporation of these derivatives into peptide models nicely illustrates their viability and applicability toward SPPS.

Structure-activity relationships in toll-like receptor 2-agonists leading to simplified monoacyl lipopeptides

Toll-like receptor 2-agonistic lipopeptides typified by S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-R-cysteinyl-S-serine (PAM2CS) compounds are potential vaccine adjuvants. In continuation of previously reported structure-activity relationships on this chemotype, we have determined that at least one acyl group of optimal length (C16) and an appropriately oriented ester carbonyl group is essential for TLR2-agonistic activity. The spacing between one of the palmitoyl ester carbonyl and the thioether is crucial to allow for an important H-bond, which observed in the crystal structure of the lipopeptide:TLR2 complex; consequently, activity is lost in homologated compounds. Penicillamine-derived analogues are also inactive, likely due to unfavorable steric interactions with the carbonyl of Ser 12 in TLR2. The thioether in this chemotype can be replaced with a selenoether. Importantly, the thioglycerol motif can be dispensed with altogether and can be replaced with a thioethanol bridge. These results have led to a structurally simpler, synthetically more accessible, and water-soluble analogue possessing strong TLR2-agonistic activities in human blood.