A pinboard by
Yesid Ramirez

Ph.D. Student, Department of Structural Biology, University of Würzburg


Molecular design of novel therapeutic alternatives against Chlamydia infections

Have you ever thought about the journey a medicine makes in your body before fulfilling its healing task? In the case of orally administered drugs like the ones we use to treat our headaches, the active pharmaceutical ingredient (the molecule, which possesses a therapeutic effect) must be absorbed and transported into the blood stream. Once there, it is free to be distributed across the body. But then, how does this molecule manage to specifically address your headache? Why does it predominantly act in certain parts of your body? And more importantly, why do some molecules have the ability to relieve pain while others are able to, for instance, cure an infection?

The easiest way to understand this is to think of your body as a complex system of “locks” and that a drug is nothing more than a “key” with the right shape complementarity to fit into one of them. Addressing the right key hole can cure a specific health disorder.

Of course, in the biochemical world there are no locks but rather an army of molecular entities known as proteins which perform different tasks to sustain life. Such tasks or activities are intimately dependent on the protein’s 3D structure (in analogy to the lock’s internal geometry). As many proteins play major roles in the progression of life threating conditions, elucidating the structure-activity relationship of proteins is essential for understanding the dynamics of human disease.

The same way a locksmith could reproduce the fine details of a key with the knowledge of the lock’s internal geometry as a template, a drug designer makes specific molecules to address the clefts and cavities of a protein given its 3D structure.

My research focuses on the structural characterization of ChlaDUB1, a protein from the pathogen Chlamydia trachomatis, which is responsible of severe sexually transmitted diseases. This protease (a protein that cleaves other proteins) is used by the bacterium as a molecular weapon to overcome the immune response of human cells upon infection, successfully increasing its harming potential.

Based on ChlaDUB1 structure similarity to the Adenovirus protease, the very first drug-like molecules able to target this protein have been identified. Our results revealed the desirable structural framework for ChlaDUB1 inhibition, which readily enables the path for structure-based drug discovery of molecules with the potential to become novel therapeutic alternatives for the treatment of Chlamydia trachomatis infections.


Deubiquitinases (DUBs) and DUB inhibitors: a patent review.

Abstract: Deubiquitinating-enzymes (DUBs) are key components of the ubiquitin-proteasome system (UPS). The fundamental role of DUBs is specific removal of ubiquitin from substrates. DUBs contribute to activation/deactivation, recycling and localization of numerous regulatory proteins, and thus play major roles in diverse cellular processes. Altered DUB activity is associated with a multitudes of pathologies including cancer. Therefore, DUBs represent novel candidates for target-directed drug development.The article is a thorough review/accounting of patented compounds targeting DUBs and stratifying/classifying the patented compounds based on: chemical-structures, nucleic-acid compositions, modes-of-action, and targeting sites. The review provides a brief background on the UPS and the involvement of DUBs. Furthermore, methods for assessing efficacy and potential pharmacological utility of DUB inhibitor (DUBi) are discussed.The FDA's approval of the 20S proteasome inhibitors (PIs): bortezomib and carfilzomib for treatment of hematological malignancies established the UPS as an anti-cancer target. Unfortunately, many patients are inherently resistant or develop resistance to PIs. One potential strategy to combat PI resistance is targeting upstream components of the UPS such as DUBs. DUBs represent a promising potential therapeutic target due to their critical roles in various cellular processes including protein turnover, localization and cellular homeostasis. While considerable efforts have been undertaken to develop DUB modulators, significant advancements are necessary to move DUBis into the clinic.

Pub.: 17 Jun '15, Pinned: 28 Aug '17

Evolutionary lines of cysteine peptidases.

Abstract: The proteolytic enzymes that depend upon a cysteine residue for activity have come from at least seven different evolutionary origins, each of which has produced a group of cysteine peptidases with distinctive structures and properties. We show here that the characteristic molecular topologies of the peptidases in each evolutionary line can be seen not only in their three-dimensional structures, but commonly also in the two-dimensional structures. Clan CA contains the families of papain (C1), calpain (C2), streptopain (C10) and the ubiquitin-specific peptidases (C12, C19), as well as many families of viral cysteine endopeptidases. Clan CD contains the families of clostripain (C11), gingipain R (C25), legumain (C13), caspase-1 (C14) and separin (C50). These enzymes have specificities dominated by the interactions of the S1 subsite. Clan CE contains the families of adenain (C5) from adenoviruses, the eukaryotic Ulp1 protease (C48) and the bacterial YopJ proteases (C55). Clan CF contains only pyroglutamyl peptidase I (C15). The picornains (C3) in clan PA have probably evolved from serine peptidases, which still form the majority of enzymes in the clan. The cysteine peptidase activities in clans PB and CH are autolytic only. In conclusion, we suggest that although almost all the cysteine peptidases depend for activity on catalytic dyads of cysteine and histidine, it is worth noting some important differences that they have inherited from their distant ancestral peptidases.

Pub.: 24 Aug '01, Pinned: 23 Aug '17