Y.J. Seo, D.A. Malyshev, T. Lavergne, P. Ordoukhanian, F.E. Romesberg, J. Am. Chem. Soc. (2011) 133:19878-19888.
We report the synthesis and analysis of the ribo- and deoxyribo-variants, (d)5SICS and (d)MMO2, modified with free or protected propargylamine linkers that allow for the site-specific modification of DNA or RNA during or after enzymatic synthesis. We also synthesized and evaluated the α-phosphorothioate variant of d5SICSTP, which provides a route to backbone thiolation and an additional strategy for the post-amplification site-specific labeling of DNA.
J. Liu, C. Luo, P.A. Smith, J.K. Chin, M.G.P. Page, M. Paetzel, F.E. Romesberg, J. Am. Chem. Soc. (2011) 133:17869-17877.
We report the first total synthesis of a lipoglycopeptide member of the arylomycin family of natural products, and we demonstrate that it effectively penetrates Gram-negative bacteria and is limited by the same resistance mechanism as other members of the arylomycin class of antibiotics (i.e. mutation in the target protein signal peptidase (SPase)). Unlike the other arylomycins, the lipoglycopeptides are glycosylated, and the structural data reveal that this sugar is most solvent exposed when in complex with SPase.
K.C. Nicolaou, S.P. Ellery, F. Rivas, K. Saye, E. Rogers, T.J. Workinger, M. Schallenberger, R. Tawatao, A. Montero, A. Hessell, F. Romesberg, D. Carson, D. Burton Bioor. Med. Chem. (2011) 19:5648-5669.
A small library of 2′,4′- and 3′,4′-bridged nucleoside analogues was synthesized and tested for antibacterial, antitumor, and antiviral activities, leading to the identification of one nucleoside that exhibited significant antiviral activity against pseudoviruses SF162 (IC50 = 7.0 μM) and HxB2 (IC50 = 2.4 μM). These findings render bridged nucleosides as credible leads for drug discovery in the anti-HIV area of research.
J. Zimmermann, M.C. Thielges, Y.J. Seo, P.E. Dawson, F.E. Romesberg, Angew. Chem. Int. Ed. (2011) 50:8333-8337.
The cyano group is sensitive to its environment, absorbs in a unique region of the protein IR spectrum, and may be appended to an amino acid. Using both steady-state and time-resolved methods, we explore the use of cyano groups as probes of protein microenvironments and dynamics in variants of cytochrome c. We find that the cyano group is a useful site-specific probe of protein microenvironments and dynamics, but that it can also perturb its environment and destabilize the folded state of the protein.
T.C. Roberts, M. Schallenberger, J. Liu, P.A. Smith, F.E. Romesberg, J. Med. Chem. (2011) 54:4954-4963.
Resistance to the arylomycins in several key human pathogens is due to the presence of a specific Pro residue in the target peptidase that disrupts interactions with the lipopeptide tail of the antibiotic. Here, we describe the synthesis and characterization of arylomycin derivatives with altered lipopeptide tails, including several with an increased spectrum of activity against S. aureus.
T.C. Roberts, P.A. Smith, F.E. Romesberg, J. Nat. Prod. (2011) 74:956-961.
We report the total synthesis of arylomycin B-C16, and its aromatic amine derivative. While the aromatic amine loses activity against all bacteria tested, the B series compound shows activities that are similar to the A series compounds, except that it also gains activity against the important pathogen Streptococcus agalactiae.
J. Zimmermann, M.C. Thielges, W. Yu, P.E. Dawson, F.E. Romesberg, J. Phys. Chem. Lett. (2011) 2:412-416.
We explore the use of carbon-deuterium (C-D) bonds under time-resolved conditions to follow the unfolding of cytochrome c from a photostationary state that accumulates after CO is photodissociated from the protein’s heme prosthetic group. Our results clearly show that C-D bonds are well-suited to characterize protein folding and dynamics.