Polyvalency: A promising strategy for drug design

Vance, David J.; Shah, Mrinal; Joshi, Amit; Kane, Ravi S.

doi:10.1002/bit.22056

Cited by 53 publications

(78 citation statements)

References 42 publications

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“…This phenomenon has a natural basis, vital to the function of binding proteins such as IgM with 10 binding sites (39) or the biological adhesion of many viruses (40), and even the extracellular matrix is polyvalent (41). Polyvalency is used frequently in the design of synthetic bioactive molecules to enhance their binding strength and has been used in the creation of bioactive peptides, organic molecules, carbohydrates, nucleotides, antibiotics, and phage mimics, among others (42)(43)(44)(45)(46). Polyvalency has even been explored for biological signaling initiated by receptor dimerization, as is the case for VEGF receptor signaling.…”

Section: Discussionmentioning

confidence: 99%

Supramolecular nanostructures that mimic VEGF as a strategy for ischemic tissue repair

Webber

Tongers

Newcomb

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

298

268

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There is great demand for the development of novel therapies for ischemic cardiovascular disease, a leading cause of morbidity and mortality worldwide. We report here on the development of a completely synthetic cell-free therapy based on peptide amphiphile nanostructures designed to mimic the activity of VEGF, one of the most potent angiogenic signaling proteins. Following self-assembly of peptide amphiphiles, nanoscale filaments form that display on their surfaces a VEGF-mimetic peptide at high density. The VEGF-mimetic filaments were found to induce phosphorylation of VEGF receptors and promote proangiogenic behavior in endothelial cells, indicated by an enhancement in proliferation, survival, and migration in vitro. In a chicken embryo assay, these nanostructures elicited an angiogenic response in the host vasculature. When evaluated in a mouse hind-limb ischemia model, the nanofibers increased tissue perfusion, functional recovery, limb salvage, and treadmill endurance compared to controls, which included the VEGF-mimetic peptide alone. Immunohistological evidence also demonstrated an increase in the density of microcirculation in the ischemic hind limb, suggesting the mechanism of efficacy of this promising potential therapy is linked to the enhanced microcirculatory angiogenesis that results from treatment with these polyvalent VEGF-mimetic nanofibers.

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Section: Discussionmentioning

confidence: 99%

Supramolecular nanostructures that mimic VEGF as a strategy for ischemic tissue repair

Webber

Tongers

Newcomb

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

298

268

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“…The design and synthesis of dimeric analogs of CQ that exploit the thermodynamic advantages imparted by polyvalency (11,12) has been previously studied in the context of malaria (13)(14)(15). The synthesis of heteroalkane-bridged bisquinolines did not produce sufficient antimalarial activity to warrant further investigation (14).…”

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confidence: 99%

Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency

McAfee¹,

Zhang²,

Samanta³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

357

313

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Autophagy is a lysosome-dependent degradative process that protects cancer cells from multiple stresses. In preclinical models, autophagy inhibition with chloroquine (CQ) derivatives augments the efficacy of many anticancer therapies, but CQ has limited activity as a single agent. Clinical trials are underway combining anticancer agents with hydroxychloroquine (HCQ), but concentrations of HCQ required to inhibit autophagy are not consistently achievable in the clinic. We report the synthesis and characterization of bisaminoquinoline autophagy inhibitors that potently inhibit autophagy and impair tumor growth in vivo. The structural motifs that are necessary for improved autophagy inhibition compared with CQ include the presence of two aminoquinoline rings and a triamine linker and C-7 chlorine. The lead compound, Lys01, is a 10-fold more potent autophagy inhibitor than HCQ. Compared with HCQ, Lys05, a water-soluble salt of Lys01, more potently accumulates within and deacidifies the lysosome, resulting in impaired autophagy and tumor growth. At the highest dose administered, some mice develop Paneth cell dysfunction that resembles the intestinal phenotype of mice and humans with genetic defects in the autophagy gene ATG16L1, providing in vivo evidence that Lys05 targets autophagy. Unlike HCQ, significant single-agent antitumor activity is observed without toxicity in mice treated with lower doses of Lys05, establishing the therapeutic potential of this compound in cancer.cell death | stress responses | cancer cell survival | drug resistance | antimalarials A utophagy, the sequestration of organelles and proteins in autophagic vesicles (AVs) and degradation of this cargo through lysosomal fusion (1), allows tumor cells to survive metabolic and therapeutic stresses (2-5). Therapy-induced autophagy is a key resistance mechanism to many anticancer agents (6), and autophagy levels are increased in most cancers (7). Chloroquine (CQ; Fig. 1, compound 1) derivatives block autophagy by impairing lysosomal function (3,8,9). Studies in multiple mouse models of malignancy have demonstrated that autophagy inhibition with CQ derivatives augments the efficacy of a variety of anticancer agents. Clinical trials combining cancer therapies with hydroxychloroquine (HCQ; Fig. 1), have been launched, and preliminary results indicate these combinations have activity (6). However, pharmacokinetic (PK)-pharmacodynamic (PD) studies conducted in patients receiving HCQ for cancer therapy have indicated that the high micromolar concentrations of HCQ required to inhibit autophagy in vitro are inconsistently achieved in humans (10). There is an unmet need to develop more potent inhibitors of autophagy.The design and synthesis of dimeric analogs of CQ that exploit the thermodynamic advantages imparted by polyvalency (11, 12) has been previously studied in the context of malaria (13-15). The synthesis of heteroalkane-bridged bisquinolines did not produce sufficient antimalarial activity to warrant further investigation (14). Subsequently, a seri...

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“…[1][2][3][4][5][6][7][8] Anthrax lethal toxin, which is responsible for the symptoms and mortality of anthrax, [9] is composed of two proteins: lethal factor (LF), an enzyme responsible for host cell death; and protective antigen (PA), which binds to cell-surface receptors and facilitates toxin internalization. Upon binding the host cell, PA is proteolytically processed into a 63 kDa fragment, PA 63 , which assembles into heptamers ((PA 63 ) 7 ) on the surface of the host cell.…”

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confidence: 99%

“…This complex formation is one of the key steps in the intoxication pathway ( Figure S1B), [10,11] and therapeutics have been designed to inhibit these interactions. [3] In previous work, phage display was used to identify a 12-mer peptide (HTSTYWWLDGAP) that binds to (PA 63 ) 7. [10] Polyvalent inhibitors have been created by attaching multiple copies of this peptide to a variety of scaffolds such as polymers, [12] liposomes, [13] and β-cyclodextrin.…”

mentioning

confidence: 99%

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Design of Monodisperse and Well‐Defined Polypeptide‐Based Polyvalent Inhibitors of Anthrax Toxin

Patke¹,

Boggara²,

Maheshwari³

et al. 2014

Angewandte Chemie

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The design of polyvalent molecules, presenting multiple copies of a specific ligand, represents a promising strategy to inhibit pathogens and toxins. The ability to control independently the valency and the spacing between ligands would be valuable for elucidating structure–activity relationships and for designing potent polyvalent molecules. To that end, we designed monodisperse polypeptide‐based polyvalent inhibitors of anthrax toxin in which multiple copies of an inhibitory toxin‐binding peptide were separated by flexible peptide linkers. By tuning the valency and linker length, we designed polyvalent inhibitors that were over four orders of magnitude more potent than the corresponding monovalent ligands. This strategy for the rational design of monodisperse polyvalent molecules may not only be broadly applicable for the inhibition of toxins and pathogens, but also for controlling the nanoscale organization of cellular receptors to regulate signaling and the fate of stem cells.

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Polyvalency: A promising strategy for drug design

Cited by 53 publications

References 42 publications

Supramolecular nanostructures that mimic VEGF as a strategy for ischemic tissue repair

Supramolecular nanostructures that mimic VEGF as a strategy for ischemic tissue repair

Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency

Design of Monodisperse and Well‐Defined Polypeptide‐Based Polyvalent Inhibitors of Anthrax Toxin

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