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Mar 1, 2011 (Vol. 31, No. 5)

Taking a Different Tack with GPCR Targets

Anchor Therapeutics' Pepducin Strategy Bypasses Problems Associated with Small Molecule Technologies

  • Click Image To Enlarge +
    Pepducins targeted toward the intracellular loops of the GPCR CXCR-4 trigger rapid clustering and internalization of the receptor into the cell. Three-dimensional reconstructions created from confocal images show that CXCR-4, in green and located on the cell surface, becomes internalized and traffics into distinct punctate endosomal structures in response to a pepducin agonist.

    The core technology platform at Anchor Therapeutics uses naturally derived lipopeptides, called pepducins, that anchor in the cell membrane and modulate GPCRs.

    Founded in 2007 as Ascent Therapeutics, the company changed its name in 2010 to better reflect its technology. Many other companies are pursuing GPCRs as drug targets, but Anchor Therapeutics’ pepducins offer a direct biological way to create drug candidates rather than the small molecule screening technologies that most competitors are pursuing, reports Frederick Jones, M.D., president and CEO. “Instead of building a better mouse trap, we’re building a better mouse.”

    Pepducins are composed of a short peptide, based on the sequence of a targeted GPCR intracellular loop, linked to a lipid moiety. Each pepducin is designed to anchor in the cell membrane and target a GPCR via a unique intracellular allosteric mechanism. Pepducins, like nautical anchors, can be customized for various purposes. GPCR activity can be positively or negatively modulated, and routes of administration can be optimized to suit a target’s profile. Pepducins hold the potential to expand the range of addressable GPCR drug targets, including orphan and intractable receptors.

    GPCRs are involved in a wide range of serious illnesses, such as inflammation, cancer, pain, central nervous system disorders, and metabolic and cardiovascular diseases. About one-third of commercialized drugs are designed to modulate GPCR function, and GPCRs are the leading molecular targets in pharmaceutical research today.

  • Discovered at Tufts

    Two scientists at the Tufts Medical Center, Lydia Covic, Ph.D., and Athan Kuliopulos, Ph.D., developed pepducins in the late 1990s. Instead of looking at GPCRs from outside the cell, they were seeking methods to target receptors on the inside surface of the cell. Initially, the Tufts scientists were studying protease-activated receptors on thrombin in platelets

    “They were the first to hit on this technique of using a piece of an intracellular domain attached to a lipid that anchors in the cell membrane so it can interact with intracellular GPCRs,” says Dr. Jones.

    Drs. Covic and Kuliopulos did not set out to discover new therapeutics; they were developing tools to study receptor signaling mechanisms. When they realized that pepducins showed drug-like characteristics that could lead to therapeutics, they filed patents to protect their discoveries.

    Each GPCR target requires a unique pepducin. A GPCR has four intracellular domains where the receptor loops back and forth across the cell membrane. “For each domain, we take different pieces of the amino acid sequence and hook them to a lipid, usually palmitate, to create a screening library of just 100 to 300 molecules,” explains Dr. Jones. Then the collection is screened for activity, and the best are optimized.

    Other companies focused on GPCRs screen large libraries with tens of thousands of randomly synthesized small chemical molecules. Because Anchor Therapeutics creates drug candidates directly from a template of peptide sequences, its libraries are smaller and highly targeted, he adds.

    Pepducins either agonize or antagonize their targets. Anchor Therapeutics claims to be one of the few companies developing agonists of GPCRs via their allosteric mechanism. One lead program focuses on designing first-in-class agonists of CXCR-4, an alpha-chemokine receptor specific for stromal-derived-factor-1. This natural ligand of CXCR-4 draws hematopoietic stem cells to the bone marrow. “By making an alternative agonist, we can set up conditions that attract stem cells to the area we’re interested in treating.”

    For instance, Anchor researchers are experimenting with injecting pepducin agonists into coronary arteries after heart attacks to attract stem cells to the ischemic tissue and promote healing. This could improve left ventricular function and reduce the incidence of congestive heart failure in the long term. Pepducin agonists that attract stem cells also lend themselves to repair of bone injuries and wound healing. “We’re highly optimistic that this approach will be beneficial,” says Dr. Jones.

    He calls the stem cell agonist approach “pharmaceutical regenerative medicine,” which eliminates the need to harvest stem cells and transplant them. “We want to take advantage of being the only agonist company we’re aware of.”

    One of Anchor’s internal programs that targets GPR39, a GPCR involved in metabolic diseases, attracted the attention of Ortho-McNeil-Janssen Pharmaceuticals (OMJPI). Under a new collaboration, the companies will work together to discover and optimize pepducins aimed at metabolic disorders and cancer. The GPR39 receptor is an orphan, meaning its natural ligand is unknown. “That makes it difficult to set up assays to screen for modulating compounds,” explains Dr. Jones. OMJPI was impressed with Anchor’s progress in designing pepducins to turn the receptor on. Anchor and OMJPI will share activities during early-stage research, then OMJPI will take over.

    Another target at Anchor is TGR5, a bile acid receptor associated with metabolic disease, lipid disorders, and some inflammatory conditions. A number of companies are looking at TGR5, but finding good chemical compounds to regulate it has proven difficult. “By coming at the receptor with pepducins, we can overcome the shortcomings.”

    For working on any GPCR target, Anchor’s pepducins provide an alternative to small chemical compounds. “Our completely different approach allows us to hit refractory or other difficult receptors, including orphans or those with natural ligands that are difficult to hit with small molecule technologies.”


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