7 research outputs found
Native Chemical Ligation−Photodesulfurization in Flow
Native chemical ligation (NCL) combined with desulfurization chemistry has revolutionized the way in which large polypeptides and proteins are accessed by chemical synthesis. Herein, we outline the use of flow chemistry for the ligation-based assembly of polypeptides. We also describe the development of a novel photodesulfurization transformation that, when coupled with flow NCL, enables efficient access to native polypeptides on time scales up to 2 orders of magnitude faster than current batch NCL–desulfurization methods. The power of the new ligation–photodesulfurization flow platform is showcased through the rapid synthesis of the 36 residue clinically approved HIV entry inhibitor enfuvirtide and the peptide diagnostic agent somatorelin.ARC Future Fellowship Scheme 25
Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis.
Tuberculosis (TB) is responsible for enormous global morbidity and mortality, and current treatment regimens rely on the use of drugs that have been in use for more than 40 years. Owing to widespread resistance to these therapies, new drugs are desperately needed to control the TB disease burden. Herein, we describe the rapid synthesis of analogues of the sansanmycin uridylpeptide natural products that represent promising new TB drug leads. The compounds exhibit potent and selective inhibition of Mycobacterium tuberculosis, the etiological agent of TB, both in vitro and intracellularly. The natural product analogues were also shown to be nanomolar inhibitors of Mtb phospho-MurNAc-pentapeptide translocase, the enzyme responsible for the synthesis of lipid I in mycobacteria. This work lays the foundation for the development of uridylpeptide natural product analogues as new TB drug candidates that operate through the inhibition of peptidoglycan biosynthesis
Synthesis of β-Thiol Phenylalanine for Applications in One-Pot Ligation- Desulfurization Chemistry
The efficient synthesis of a β-thiol phenylalanine derivative is described starting from Garner’s aldehyde. The utility of this amino acid in peptide ligation–desulfurization chemistry is described, including the trifluoroethanethiol (TFET)-promoted one-pot assembly of the 62 residue peptide hormone augurin
Native Chemical Ligation–Photodesulfurization in Flow
Native
chemical ligation (NCL) combined with desulfurization chemistry
has revolutionized the way in which large polypeptides and proteins
are accessed by chemical synthesis. Herein, we outline the use of
flow chemistry for the ligation-based assembly of polypeptides. We
also describe the development of a novel photodesulfurization transformation
that, when coupled with flow NCL, enables efficient access to native
polypeptides on time scales up to 2 orders of magnitude faster than
current batch NCL–desulfurization methods. The power of the
new ligation–photodesulfurization flow platform is showcased
through the rapid synthesis of the 36 residue clinically approved
HIV entry inhibitor enfuvirtide and the peptide diagnostic agent somatorelin
Total Synthesis of Teixobactin
The first total synthesis of the
cyclic depsipeptide natural product
teixobactin is described. Synthesis was achieved by solid-phase peptide
synthesis, incorporating the unusual l-<i>allo</i>-enduracididine as a suitably protected synthetic cassette and employing
a key on-resin esterification and solution-phase macrolactamization.
The synthetic natural product was shown to possess potent antibacterial
activity against a range of Gram-positive pathogenic bacteria, including
a virulent strain of <i>Mycobacterium tuberculosis</i> and
methicillin-resistant <i>Staphylococcus aureus</i> (MRSA)
Development of supramolecular anticoagulants with on-demand reversibility
Drugs are administered at a dosing schedule set by their therapeutic index, and termination of action is achieved by clearance and metabolism of the drug. In some cases, such as anticoagulant drugs or immunotherapeutics, it is important to be able to quickly reverse the drug’s action. Here, we report a general strategy to achieve on-demand reversibility by designing a supramolecular drug (a noncovalent assembly of two cooperatively interacting drug fragments held together by transient hybridization of peptide nucleic acid (PNA)) that can be reversed with a PNA antidote that outcompetes the hybridization between the fragments. We demonstrate the approach with thrombin-inhibiting anticoagulants, creating very potent and reversible bivalent direct thrombin inhibitors ( K i = 74 pM). The supramolecular inhibitor effectively inhibited thrombus formation in mice in a needle injury thrombosis model, and this activity could be reversed by administration of the PNA antidote. This design is applicable to therapeutic targets where two binding sites can be identified.</p