Interfacial inhibitors: targeting macromolecular complexes

Key Points Interfacial inhibitors belong to a broad class of natural products and synthetic drugs that are commonly used to treat cancers as well as bacterial and HIV infections. They bind selectively to interfaces as macromolecular machines assemble and are set in motion. The bound drugs transiently arrest the targeted molecular machines and desynchronize their concerted functions. To provide an operational (empirical) definition of interfacial inhibition, we present five archetypical examples of interfacial inhibitors: the camptothecins, etoposide, the quinolone antibiotics, the vinca alkaloids and the novel anti-HIV inhibitor raltegravir. We discuss the common and diverging elements between interfacial and allosteric inhibitors, and demonstrate that interfacial inhibitors can also be classified as orthosteric and allosteric inhibitors. Finally, we give a perspective and provide specific examples for the rationale and methods to discover novel interfacial inhibitors. Interfacial inhibitors bind to the interfaces of macromolecular machines (for example, polymerases or ribosomes) and stall their progress. A number of natural product and synthetic interfacial inhibitors are in the clinic for the treatment of cancer and bacterial infections. Here, Pommier and Marchand review the concept of interfacial inhibition, and discuss the rationale and methods for the discovery of novel interfacial inhibitors. Interfacial inhibitors belong to a broad class of natural products and synthetic drugs that are commonly used to treat cancers as well as bacterial and HIV infections. They bind selectively to interfaces as macromolecular machines assemble and are set in motion. The bound drugs transiently arrest the targeted molecular machines, which can initiate allosteric effects, or desynchronize macromolecular machines that normally function in concert. Here, we review five archetypical examples of interfacial inhibitors: the camptothecins, etoposide, the quinolone antibiotics, the vinca alkaloids and the novel anti-HIV inhibitor raltegravir. We discuss the common and diverging elements between interfacial and allosteric inhibitors and give a perspective for the rationale and methods used to discover novel interfacial inhibitors.