Peptide inhibitors of phosphoglycerate mutase and methods of use

Inventors

Inglese, James • Dranchak, Patricia • MacArthur, Ryan • Suga, Hiroaki • Yu, Hao • Carlow, Clotilde • Li, Zhiru

Assignees

University of Tokyo NUC • New England Biolabs Inc • US Department of Health and Human Services

Abstract

Disclosed herein are isolated peptides inhibit activity of a cofactor-independent phosphoglycerate mutase. In some examples, the isolated peptide is 6-20 amino acids long and includes the amino acid sequence of any one of SEQ ID NOs: 1-22 or 54, an analog or derivative thereof, or a pharmaceutically acceptable salt or ester thereof. In some examples, the peptide is a cyclic peptide with an N-terminal ring of 6-15 amino acids (for example, 6-10 amino acids) and a C-terminal linear portion of 1-9 amino acids (for example, 3-8 amino acids. Also disclosed h are methods of treating or inhibiting an infection in a subject, including administering to the subject an effective amount of a composition including one of more of the disclosed peptides, or analogs or derivative thereof, or pharmaceutically acceptable salts or esters thereof.

Core Innovation

Disclosed herein are isolated peptides that inhibit activity of a cofactor-independent phosphoglycerate mutase (iPGM). The peptides are 6-20 amino acids long and include the amino acid sequence of any one of SEQ ID NOs: 1-22 or 54-69, analogs or derivatives thereof, or pharmaceutically acceptable salts or esters thereof. In some examples, the peptides are cyclic peptides with an N-terminal ring structure of 6-15 amino acids and a C-terminal linear portion of 1-9 amino acids. The peptides can selectively inhibit activity of iPGM compared to cofactor-dependent PGM (dPGM). The compounds and compositions including these peptides are useful in methods of treating or inhibiting an infection in a subject, involving administration of an effective amount of the peptide or composition.

Parasitic nematode infection causes devastating diseases such as lymphatic filariasis and onchocerciasis affecting millions worldwide and leading to severe clinical symptoms. The control of filarial diseases has relied mainly on a limited number of drugs, which have issues such as targeting mainly larval stages, requiring frequent administration, and emerging drug resistance. Thus, there is a need for new drugs with novel modes of action. The invention addresses this need by targeting the nematode enzyme iPGM, an essential enzyme absent in humans, making it a promising selective drug target.

The peptides disclosed include unique lariat-structured cyclic peptides that were identified from a trillion-member library using mRNA display technologies. The peptides exhibit potent and isozyme-selective inhibition against iPGMs from a range of species. Structural studies reveal binding at a cleft formed by the phosphatase and transferase domains of iPGM, with evidence for a cooperative binding mechanism involving the macrocycle and the C-terminal tail coordinating to metal ions at the enzyme active site. Such inhibitors overturn previous beliefs of iPGM as an "undruggable" target, providing a novel class of anti-microbial therapeutics for infections caused by nematodes, bacteria, and protozoan parasites.

Claims Coverage

The patent includes multiple independent claims centered on isolated cyclic peptides and methods of use. Main inventive features cover specific peptide structures, modifications, inhibitory activity, pharmaceutical compositions, and therapeutic methods.

The claims cover isolated cyclic peptides with defined sequences and cyclization linkages that selectively inhibit iPGM, pharmaceutical compositions containing them, and methods of treating infections by administering these peptides to subjects, focusing on nematode and microbial pathogens.

Stated Advantages

Documented Applications