Convergent diversity-oriented side-chain macrocyclization scan for unprotected polypeptides

Here we describe a general synthetic platform for side-chain macrocyclization of an unprotected peptide library based on the S[subscript N]Ar reaction between cysteine thiolates and a new generation of highly reactive perfluoroaromatic small molecule linkers. This strategy enabled us to simultaneously “scan” two cysteine residues positioned from i, i + 1 to i, i + 14 sites in a polypeptide, producing 98 macrocyclic products from reactions of 14 peptides with 7 linkers. A complementary reverse strategy was developed; cysteine residues within the polypeptide were first modified with non-bridging perfluoroaryl moieties and then commercially available dithiol linkers were used for macrocyclization. The highly convergent, site-independent, and modular nature of these two strategies coupled with the unique chemoselectivity of a S[subscript N]Ar transformation allows for the rapid diversity-oriented synthesis of hybrid macrocyclic peptide libraries with varied chemical and structural complexities.National Institutes of Health (U.S.) (GM101762)National Institutes of Health (U.S.) (GM046059)MIT Faculty Start-up FundSontag Foundation (Distinguished Scientist Award)Deshpande Center for Technological InnovationMassachusetts Institute of Technology (Charles E. Reed Faculty Initiative Fund)Damon Runyon Cancer Research Foundatio

A New Control Logic for a Wind-Area on the Balancing Authority Area Control Error Limit Standard for Load Frequency Control

Nowadays, the Balancing Authority Area Control Error (ACE) Limit (BAAL) Standard has been adopted to replace the Control Performance Standard 2 (CPS2) in the North American power grid. According to the new standard’s mechanism, a new control logic, named “Triggered Monitoring and Graded Regulation” (TM-GR) is proposed. Its purpose is to improve wind power utilization, with good BAAL Standard compliance for load frequency control (LFC). With the TM logic, according to the real-time regulating ability of areas and forecasting results of wind power output, the triggering moments to give orders are found and a defined monitoring interval is set to track the succeeding fluctuation of Area Control Error (ACE). With the GR logic, based on whether or not over-limit frequency and over-limit ACE occur simultaneously, unit output is regulated in different grades. In cooperation with the existing control logic of Control Performance Standard 1 (CPS1), the proposed logic has a higher priority. From the test results, with the proposed control logic, the utilization of wind power output increases and, meanwhile, the area’s control performance meets the Standard BAL-001-2 requirements. The standard deviation of the frequency deviation is less than the target value, and the duration of over-limit ACE and over-limit frequency can both be restricted to be less than 30 min

A Perfluoroaryl-Cysteine S[subscript N]Ar Chemistry Approach to Unprotected Peptide Stapling

We report the discovery of a facile transformation between perfluoroaromatic molecules and a cysteine thiolate, which is arylated at room temperature. This new approach enabled us to selectively modify cysteine residues in unprotected peptides, providing access to variants containing rigid perfluoroaromatic staples. This stapling modification performed on a peptide sequence designed to bind the C-terminal domain of an HIV-1 capsid assembly polyprotein (C-CA) showed enhancement in binding, cell permeability, and proteolytic stability properties, as compared to the unstapled analog. Importantly, chemical stability of the formed staples allowed us to use this motif in the native chemical ligation-mediated synthesis of a small protein affibody that is capable of binding the human epidermal growth factor 2 receptor.National Institutes of Health (U.S.) (GM046059)National Institutes of Health (U.S.) (GM101762)MIT Faculty Start-up FundSingapore. Agency for Science, Technology and Research (National Science Scholarship)National Cancer Institute (U.S.) (P30-CA14051

A Perfluoroaryl-Cysteine S_NAr Chemistry Approach to Unprotected Peptide Stapling

We report the discovery of a facile transformation between perfluoroaromatic molecules and a cysteine thiolate, which is arylated at room temperature. This new approach enabled us to selectively modify cysteine residues in unprotected peptides, providing access to variants containing rigid perfluoroaromatic staples. This stapling modification performed on a peptide sequence designed to bind the C-terminal domain of an HIV-1 capsid assembly polyprotein (C-CA) showed enhancement in binding, cell permeability, and proteolytic stability properties, as compared to the unstapled analog. Importantly, chemical stability of the formed staples allowed us to use this motif in the native chemical ligation-mediated synthesis of a small protein affibody that is capable of binding the human epidermal growth factor 2 receptor

A Perfluoroaryl-Cysteine S_NAr Chemistry Approach to Unprotected Peptide Stapling

We report the discovery of a facile transformation between perfluoroaromatic molecules and a cysteine thiolate, which is arylated at room temperature. This new approach enabled us to selectively modify cysteine residues in unprotected peptides, providing access to variants containing rigid perfluoroaromatic staples. This stapling modification performed on a peptide sequence designed to bind the C-terminal domain of an HIV-1 capsid assembly polyprotein (C-CA) showed enhancement in binding, cell permeability, and proteolytic stability properties, as compared to the unstapled analog. Importantly, chemical stability of the formed staples allowed us to use this motif in the native chemical ligation-mediated synthesis of a small protein affibody that is capable of binding the human epidermal growth factor 2 receptor