An Antibody-Recruiting Small Molecule That Targets HIV gp120

Abstract

HIV/AIDS is a global pandemic for which new treatment strategies are desperately needed. We have designed a novel small molecule with the potential to interfere with HIV survival through two mechanisms: (1) by recruiting antibodies to gp120-expressing virus particles and infected human cells, thus enhancing their uptake and destruction by the human immune, and (2) by binding the viral glycoprotein gp120, inhibiting its interaction with the human protein CD4, and preventing virus entry. Here we demonstrate that ARM-H is capable of simultaneously binding gp120, a component of the Env surface viral glycoprotein (found on the surface of both HIV and virus-infected cells) and anti-2,4-dinitrophenyl antibodies (already present in the human bloodstream). The ternary complex formed between antibody, ARM-H, and gp120 is immunologically active and leads to the complement-mediated destruction of Env-expressing cells. Furthermore, ARM-H prevents virus entry into human T-cells, and should therefore be capable of inhibiting virus replication through two mutually reinforcing mechanisms (inhibition of virus entry and antibody-mediated killing). These studies demonstrate the viable anti-HIV activity of antibody-recruiting small molecules, and have the potential to initiate novel paradigms in HIV treatment.

Highly potent, synthetically accessible prostratin analogs induce latent HIV expression in vitro and ex vivo

“…Treatment of the ketone (7) with hydrazine hydrate forms a hydrazone, which upon heating with diisopropylethyl amine in toluene cyclizes to an air-sensitive pyrazoline. After cyclization is complete, the reaction mixture is cooled to −78°C and treated with a solution of lead tetraacetate in dichloromethane to afford the oxidized cyclic diazene (8) in an isolated yield of up to 59% over two steps from trityl-crotophorbolone. The use of toluene in combination with diisopropylethyl amine instead of pyridine allows the cyclization and oxidation reactions to be conducted in one flask, thus shortening the synthetic route.…”

“…For this approach, it has been proposed that certain agents might be used in combination with HAART to induce HIV activation and therefore depletion of reservoir cells through a cytopathic effect associated with virus production. It is also possible that a combination of inducers and HIV-specific agents would provide a complementary or synergistic strategy for clearance of infected cells (8,9). Immunotoxins, for example, consisting of an antibody to target the HIV envelope protein on the surface of productively infected cells (10) and toxins to kill the cell, represent one strategy to eliminate reservoirs more effectively in conjunction with latency activating agents.…”

Illuminating HIV gp120-ligand recognition through computationally-driven optimization of antibody-recruiting molecules

“…To this end, our laboratory has developed a class of anti-HIV compounds termed antibody-recruiting molecules targeting HIV (ARM-Hs). 1 …”

Prevalence and Gene Characteristics of Antibodies with Cofactor-induced HIV-1 Specificity

“…A fraction of Abs in normal serum also bind with high affinity to several xenobiotic organic compounds such as dinitrophenyl and naphthalene derivatives, as well as azo compounds (8 -12). The presence of cofactorbinding Abs in normal human immune repertoires has been recently used for specific targeting of cancer cells or viruses as well as for catalysis of redox reactions, thus demonstrating the possibility to develop innovative therapeutic strategies based on cofactor-binding Abs (13)(14)(15)(16)(17). However, the origin, molecular characteristics, and physiopathological significance of natural cofactor-binding Abs in human immune repertoires remain not well understood.…”