Identification and characterization of 3-substituted pyrazolyl esters as alternate substrates for cathepsin B: The confounding effects of DTT and cysteine in biological assays

Substituted pyrazole esters were identified as hits in a high throughput screen (HTS) of the NIH Molecular Libraries Small Molecule Repository (MLSMR) to identify inhibitors of the enzyme cathepsin B. Members of this class, along with functional group analogs, were synthesized in an effort to define the structural requirements for activity. Analog characterization was hampered by the need to include a reducing agent such as dithiothreitol (DTT) or cysteine in the assay, highlighting the caution required in interpreting biological data gathered in the presence of such nucleophiles. Despite the confounding effects of DTT and cysteine, our studies demonstrate that the pyrazole 1 acts as alternate substrate for cathepsin B, rather than as an inhibitor

The Story of Black Scientists Born in the 19th Century

The technological innovations developed in Africa have an important place in the history of invention and date back to the ancient world. Africans had a knowledge of astronomy, agricultural science, engineering, and medicine based on natural plant products. Although this knowledge was often more developed in Africa than anywhere else in the world, African contributions were mostly ignored by the rest of the world. Many contributions of Blacks to modern technology are still not widely known. In 1913 alone, more than a thousand inventions were patented by African Americans who were fortunate enough to be accepted at the patent office. Many other black inventors discovered medicines as well as laborsaving devices, but were not allowed to patent them in their own names; others who controlled their labor stole credit, authorship, and profit for their discoveries. In this article, we hope to inspire young people of all colors by telling the stories of black scientists who developed products, medicines, and systems that changed lives. All scientists presented here were born before the 20th century, when Blacks were up against severe forms of oppression and inhumanity. Black people faced unparalleled obstacles in accessing both primary and higher education, and the few educational facilities that were available to Blacks were inadequate compared to those available to whites. Additionally, black people could not obtain housing or jobs, and they were not recognized or included as members of society. Despite these challenges, some of the greatest scientific discoveries were made by black people. The black scientists highlighted here did not have equal access to education during their lifetime, and it was only through perseverance that they were able to overcome obstacles and earn educational degrees. We highlight the scientific discoveries made by some of the most brilliant black scientists during this era, depicting how racist laws and practices affected them, and we discuss them chronologically by their date of birth to identify the social changes that occurred over the years

Small-molecule inhibitors of integrin α2β1 that prevent pathological thrombus formation via an allosteric mechanism

There is a grave need for safer antiplatelet therapeutics to prevent heart attack and stroke. Agents targeting the interaction of platelets with the diseased vessel wall could impact vascular disease with minimal effects on normal hemostasis. We targeted integrin α2β1, a collagen receptor, because its overexpression is associated with pathological clot formation whereas its absence does not cause severe bleeding. Structure–activity studies led to highly potent and selective small-molecule inhibitors. Responses of integrin α2β1 mutants to these compounds are consistent with a computational model of their mode of inhibition and shed light on the activation mechanism of I-domain-containing integrins. A potent compound was proven efficacious in an animal model of arterial thrombosis, which demonstrates in vivo efficacy for inhibition of this platelet receptor. These results suggest that targeting integrin α2β1 could be a potentially safe, effective approach to long-term therapy for cardiovascular disease