TRPV1-targeted ligand-drug conjugates to treat prostate cancer

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Development of antibody-directed therapies: quo vadis?

Publication . Rodrigues, Tiago; Bernardes, Gonçalo J. L.

Less is more: The efficacy of antibody-drug conjugates (ADCs) for cancer therapy is traditionally associated with cleavable linkers for payload release. Evidence now suggests that simpler constructs without cleavable moieties can afford more stable and effective ADCs.

2018Journal article

Open access

A water-bridged cysteine-cysteine redox regulation mechanism in bacterial protein tyrosine phosphatases

Publication . Bertoldo, Jean B.; Rodrigues, Tiago; Dunsmore, Lavinia; Aprile, Francesco A.; Marques, Marta C.; Rosado, Leonardo A.; Boutureira, Omar; Steinbrecher, Thomas B.; Sherman, Woody; Corzana, Francisco; Terenzi, Hernán; Bernardes, Gonçalo J. L.

The emergence of multidrug-resistant Mycobacterium tuberculosis (Mtb) strains highlights the need to develop more efficacious and potent drugs. However, this goal is dependent on a comprehensive understanding of Mtb virulence protein effectors at the molecular level. Here, we used a post-expression cysteine (Cys)-to-dehydrolanine (Dha) chemical editing strategy to identify a water-mediated motif that modulates accessibility of the protein tyrosine phosphatase A (PtpA) catalytic pocket. Importantly, this water-mediated Cys-Cys non-covalent motif is also present in the phosphatase SptpA from Staphylococcus aureus, which suggests a potentially preserved structural feature among bacterial tyrosine phosphatases. The identification of this structural water provides insight into the known resistance of Mtb PtpA to the oxidative conditions that prevail within an infected host macrophage. This strategy could be applied to extend the understanding of the dynamics and function(s) of proteins in their native state and ultimately aid in the design of small-molecule modulators.

2017Journal article

Open access