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Potent Inhibition of HIV‐1 Entry with a Chemically Programmed Antibody Aided by an Efficient Organocatalytic Synthesis

Innovative new approaches to HIV-1 prophylaxis and therapy are desperately needed. Despite the successes of highly active antiretroviral therapy (HAART), more than two million people die each year from HIV-1 infection, and over 33 million individuals are infected worldwide. [1] Current anti-HIV therapies rely mainly on targeting viral proteins involved in replication; drugresistant viral strains rapidly evolve in the face of this type of therapy. A promising alternative to the targeting of viral proteins is the targeting of host proteins required for viral entry and replication. Unlike viral proteins, host proteins are not under selective pressure to evolve to evade the therapeutic agent. The most advanced approaches in this area target the HIV-1 entry coreceptor CCR5. [2] FDA approval of the CCR5 blocking drug Maraviroc in 2007 is one of the most recent breakthroughs in anti-HIV therapy. [3] As part of a program to build novel long-lived and potent HIV therapeutics, we have chemically programmed an antibody using a small molecule drug that targets the CCR5 G protein-coupled receptor. Chemically programmed antibodies (cpAbs) represent a new class of biologic drugs that acquire their specificity through chemistry rather than through biology. [4] Although several cpAbs are now in clinical trials for the treatment of a variety of diseases, the application of this technology to small molecules that target the very important class of drug targets represented by G protein-coupled receptors has not been reported. We selected Aplaviroc as our CCR5 targeting compound based on its extensive characterization and potent activity against a wide range of laboratory and primary isolates of HIV-1. [5] Aplaviroc also displays an intriguing pharmacology that might allow us in future studies to probe the potential of the chemically programmed antibody approach to correct pharmacological issues of small molecules, such as metabolic toxicity. [6] In order to create a chemically programmed antibody that targets CCR5, a derivative of Aplaviroc that allows for its attachment to the active site of cpAb while maintaining CCR5 binding, was designed. Homology modeling of the CCR5 receptor and docking studies of Aplaviroc into the putative binding pocket suggested that the carboxylic acid end points toward the solvent and is not crucial for interaction with the receptor. [7] This modeling data, together with analysis of the structure‐activity relationship (SAR) of Aplaviroc derivatives led us to the hypothesis that the carboxylic acid group of Aplaviroc could be conjugated to a linker to enable attachment to a chemically programmable antibody without compromising the binding activity of the parent molecule. In order to test this hypothesis, we designed a new synthesis strategy to access derivatives of Aplaviroc. In our study of the reported synthesis of Aplaviroc, [8] we noted an important challenge that could be overcome with organocatalysis. The key step to the synthesis of Aplaviroc is generation of the (R,R)-cyclohexylserine moiety. Although several excellent methods have been established in industry, including kinetic dynamic resolution by catalytic hydrogenation [8d] and enzymatic reduction, [8e] these approaches require high pressure, low tempera