Synthesis and evaluation of TAC-based inhibitors of papain as mimics of cystatin B

Chembiochem : a European Journal of Chemical Biology
Dirk-Jan van ZoelenRob M J Liskamp

Abstract

An approach for mimicking protein-protein interactions by using a discontinuous epitope to construct a mimic that is about one tenth of the size of a natural inhibitor of papain, namely, cystatin B, is described. The discontinuous epitope of cystatin B, which is involved in the interaction with papain, was mimicked by synthesis of a tripodal molecular construct by using the triazacyclophane (TAC) scaffold. The mimic contains three peptide arms: one that mimics the N terminus, one that mimics the C terminus, and one that mimics the beta-hairpin loop structure of cystatin B. These peptide sequences were assembled on the TAC scaffold. The resulting cystatin mimic, CysTACtin 9, showed excellent inhibition of papain with a K(i) of 12 nM, which approaches the inhibitory potency of cystatin B (K(i)=0.12 nM). Experiments with molecular constructs that contained one or two arms or a mixture of the nonscaffolded peptides showed that both scaffolding and the presence of the three peptide arms are crucial for a successful mimic.

References

May 14, 1992·Nature·T J MolinaA Veillette
Jul 22, 1991·FEBS Letters·V Turk, W Bode
Apr 5, 1985·Biochimica Et Biophysica Acta·S ZuckerA J Barrett
Jun 1, 1974·The Biochemical Journal·R Eisenthal, A Cornish-Bowden
Sep 29, 1999·Proceedings of the National Academy of Sciences of the United States of America·P M SelzerJ H McKerrow
Dec 26, 2001·Chemical Reviews·M W Peczuh, Andrew D Hamilton
Mar 29, 2002·Chembiochem : a European Journal of Chemical Biology·Frank J DekkerRob M J Liskamp
Jun 5, 2002·Nature Reviews. Cancer·Harald zur Hausen
Aug 23, 2003·Trends in Biochemical Sciences·Phoebe Harjes, Erich E Wanker
Jun 24, 2004·Molecular Diversity·Rishi JainAndrew D Hamilton
Sep 30, 2004·Organic & Biomolecular Chemistry·Raimo FrankeJ Eichler
Jun 15, 2005·Angewandte Chemie·Hang Yin, Andrew D Hamilton

Citations

Jan 17, 2012·Journal of Medicinal Chemistry·Christopher J ArnuschYechiel Shai
Sep 1, 2012·Chemical Communications : Chem Comm·Gwenn E MulderRob M J Liskamp
Oct 22, 2008·Current Opinion in Chemical Biology·Jutta Eichler

Related Concepts

Antigenic Specificity
Aza Compounds
Cyclization
Enzyme Inhibitors
Tromasin
Structure-Activity Relationship
Cystatin-Related Proteins
Tertiary Protein Structure
Cystatin B

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Systemic Juvenile Idiopathic Arthritis

Systemic juvenile idiopathic arthritis is a rare rheumatic disease that affects children. Symptoms include joint pain, but also fevers and skin rashes. Here is the latest on this disease.

Chromatin Regulation and Circadian Clocks

The circadian clock plays an important role in regulating transcriptional dynamics through changes in chromatin folding and remodelling. Discover the latest research on Chromatin Regulation and Circadian Clocks here.

Central Pontine Myelinolysis

Central Pontine Myelinolysis is a neurologic disorder caused most frequently by rapid correction of hyponatremia and is characterized by demyelination that affects the central portion of the base of the pons. Here is the latest research on this disease.

Myocardial Stunning

Myocardial stunning is a mechanical dysfunction that persists after reperfusion of previously ischemic tissue in the absence of irreversible damage including myocardial necrosis. Here is the latest research.

Pontocerebellar Hypoplasia

Pontocerebellar hypoplasias are a group of neurodegenerative autosomal recessive disorders with prenatal onset, atrophy or hypoplasia of the cerebellum, hypoplasia of the ventral pons, microcephaly, variable neocortical atrophy and severe mental and motor impairments. Here is the latest research on pontocerebellar hypoplasia.

Cell Atlas Along the Gut-Brain Axis

Profiling cells along the gut-brain axis at the single cell level will provide unique information for each cell type, a three-dimensional map of how cell types work together to form tissues, and insights into how changes in the map underlie health and disease of the GI system and its crosstalk with the brain. Disocver the latest research on single cell analysis of the gut-brain axis here.

Chronic Traumatic Encephalopathy

Chronic Traumatic Encephalopathy (CTE) is a progressive degenerative disease that occurs in individuals that suffer repetitive brain trauma. Discover the latest research on traumatic encephalopathy here.