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ACS Medicinal Chemistry Letters
 
ACS Med Chem Lett. 2016 March 10; 7(3): 204.
Published online 2016 March 10. doi:  10.1021/acsmedchemlett.6b00085
PMCID: PMC4789674

In This Issue, Volume 7, Issue 3

Addressing the Cathepsin B Occluding Loop with Click Chemistry

Cathepsin B is a cysteine protease that is normally localized in the lysosome but is found at the surface of invasive tumor cells where it acts in the degradation of extracellular matrix. Given its established role in contributing to invasive disease, cathepsin B has been proposed as a biomarker for prediction of aggressive disease in a number of cancers including endometrial cancer and breast cancer.

Cathepsin B is a cysteine protease that is normally localized in the lysosome but is found at the surface of invasive tumor cells where it acts in the degradation of extracellular matrix. Given its established role in contributing to invasive disease, cathepsin B has been proposed as a biomarker for prediction of aggressive disease in a number of cancers including endometrial cancer and breast cancer. Effective inhibitors of cathepsin B are being investigated for their potential as targeted cancer therapeutics.

In this issue’s Featured Letter, Schmitz el al. (DOI: 10.1021/acsmedchemlett.5b00474) screen a library of 57 dipeptide nitriles to map the active site of human cathepsin B. The results of the screen are used to guide the synthesis of new inhibitors, with click chemistry being used to address the occluding loop. The authors evaluate inhibition of the cathepsin B endopeptidase or exopeptidase activities and identify a lead compound for further development as a potent and selective cathepsin B inhibitor.

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Designing New and Improved CD4 Mimics

Despite major advances in treatment of HIV, which have greatly improved the quality of life of infected individuals, no effective vaccine or cure is available, and so, strategies to prevent HIV transmission and reduce of viral load in infected patients are needed.

Despite major advances in treatment of HIV, which have greatly improved the quality of life of infected individuals, no effective vaccine or cure is available, and so, strategies to prevent HIV transmission and reduce of viral load in infected patients are needed. As HIV specifically targets and depletes the CD4 cells of the immune system, small-molecule CD4 mimics present an attractive option for therapeutic development.

Here, Melillo et al. (DOI: 10.1021/acsmedchemlett.5b00471) describe the design, synthesis, and evaluation of small-molecule CD4-mimics that inhibit HIV-1 entry with greater potency than previously reported inhibitors particularly against a neutralization-resistant strain. Using computational, thermodynamic, and crystallographic data for the design of the CD4 mimics, this study illustrates the utility of molecular design strategies that exploit static crystallographic protein–ligand structures and in silico modeling, even when they involve an intrinsically dynamic protein such as the HIV-1 Env.

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Developing of Safer and Effective Drugs for Schizophrenia

Glutamate is an excitatory neurotransmitter in the brain and dysfunction in the glutamate system has been implicated in schizophrenia. Currently available antipshychotic drugs for treatment of schizophrenia suffer from a number of side effects, and so, effective options with reduced side effects present an exciting prospect for individuals suffering from this serious disorder.

Glutamate is an excitatory neurotransmitter in the brain and dysfunction in the glutamate system has been implicated in schizophrenia. Currently available antipshychotic drugs for treatment of schizophrenia suffer from a number of side effects, and so, effective options with reduced side effects present an exciting prospect for individuals suffering from this serious disorder. The metabotropic glutamate receptor subtype 5 (mGluR5) is expressed throughout the central nervous system, and positive regulation of this receptor has been suggested as a strategy for therapeutic development for schizophrenia. Nonetheless, mGluR5 has been a challenging target due to concerns regarding potential toxicity and adverse effects.

In this issue, Yang et al. (DOI: 10.1021/acsmedchemlett.5b00450) report the optimization of a selective mGluR5 positive allosteric modulator (PAM). The authors describe critical properties of the mGluR5 PAM that are required to achieve both safety and efficacy allowing the compound to advance into preclinical development for evaluation as a candidate for treatment of schizophrenia.

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Articles from ACS Medicinal Chemistry Letters are provided here courtesy of American Chemical Society