Protease Inhibitors in the Clinic

Abstract

This review describes the clinical status (based on available information) of experimental drugs that inhibit enzymes called proteases, or more precisely a sub-class of proteases called peptidases that catalyse the hydrolysis of polypeptide main chain amide bonds. These peptidases are classified by the key catalytic residue in the active site of the enzyme that effects hydrolysis, namely aspartic, serine, cysteine, metallo or threonine proteases. In this review we show structures for 108 inhibitors of these enzymes and update the clinical disposition of over 100 inhibitors that have been considered worthy enough by pharmaceutical, biotechnology or academic researchers and their financial backers to be trialed in humans as prospective medicines. We outline some of their chemical and pharmacological characteristics and compare the current status of protease inhibitors in the clinic with what was observed about 5 years ago (Leung et al, J. Med. Chem. 2000, 43, 305-341). We assess the progress of protease inhibitors into man, predict their futures, and outline some of the hurdles that have been overcome and that still remain for this promising class of new therapeutic agents.

The interplay between the proteolytic, invasive, and adhesive domains of invadopodia and their roles in cancer invasion

“…Treating cancer with MMP inhibitors was considered to be a very promising approach and was studied in a variety of clinical trials as therapy for various types of cancers. [57][58][59] Unfortunately, those trials were largely unsuccessful, most likely due to the development of drug resistance by the tumor cells, 60 secretion of MMP from stroma cells around the tumor, 61 lack of sufficient specificity of the inhibitors, and changes in the cancer cell migration and invasion mechanism, capable of switching from proteolysis-dependent migration to amoeboid migration (a so-called "mesenchymal-amoeboid transition"). 50,62 The failure of MMP inhibition to block cancer invasion indicates that the remodeling of the ECM per se is not sufficient for preventing cancer invasion and metastasis, and suggests that cell invasion into the matrix requires an active migratory process, whereby cancer cells "force their way" into the matrix.…”

Impedance Method for Detecting HIV-1 Protease and Screening For Its Inhibitors Using Ferrocene−Peptide Conjugate/Au Nanoparticle/Single-Walled Carbon Nanotube Modified Electrode

“…It has been known that indinavir is potent and competitively inhibits HIV-1PR with a K i value of 0.52 nM. 29 A similar value (0.571 ± 0.143 nM) was reported for this inhibitor, compared to 67.3 ± 5.2 pM for saquinavir. 30 Two FDA approved commercial drugs tested in this study, lopinavir/ritonavir and fosamprenavir, were dissolved in the buffer solution and examined in situ without any further purification.…”

“…The inhibitory constant (K i ) for amprenavir is 0.6 nM whereas fosamprenavir is not considered as a potent inhibitor for HIV-1 PR. 29 Hence, fosamprenavir was used as a control in this study. As expected, even at 1 nM, fosamprenavir did not bind to HIV-1 PR, compared to the other three inhibitors (Figure 6).…”

Screening of Protease Inhibitory Activity in Aqueous Extracts of Marine Invertebrates from Cuban Coast

“…These enzymes are involved in a broad range of physiological processes of vital importance, including defense mechanisms in response to infection, activation of prohormones and zymogens, release of active peptides, assembly of viruses and proliferation/invasion processes of bacteria and parasites [1] [3]. Many examples show the functional role of proteases in the appearance or development of diseases [2] [4], e.g.…”