Molecular-Genetic Imaging
Martin G. Pomper, Juri G. Gelovani, Benjamin Tsui, Kathleen Gabrielson, Richard Wahl, S. Sam Gambhir, Jeff Bulte, Raymond Gibson, William C. Eckelman in Molecular Imaging in Oncology, 2008
Because of better spectral properties of near-infrared light leading to increased tissue penetration and reduced autofluorescence, near-infrared fluorescence (NIRF) is gaining increased attention. Whereas visible light penetration in tissues is only 1 to 2 mm, near-infrared light with wavelengths of 700 to 1.2 nm enables better penetration into tissues (73). The recent advances in NIRF imaging have been accelerated by the development of NIR fluorochromes coupled to quenching peptides that are activated by specific proteases at the target site (26). Such proteases can also be used as reporter genes as was demonstrated by Shah et al. (74) for the viral HIV-1 protease (HIV-1 PR). The authors showed specific fluorescence activation of a HIV-1 PR specific NIRF probe in human Gli36 gliomas after injection with an HSV-1 amplicon vector expressing HIV-1 PR. Essential for the development of reporter protease/substrate systems is the fact that the protease is not ubiquitously expressed in mammalian tissue as is the case by the use of viral proteases.
Targeting Human T-Cell Leukemia Virus Type 1
Satya Prakash Gupta in Cancer-Causing Viruses and Their Inhibitors, 2014
Because the HTLV-1 protease is responsible for cleavage of the Gag and Pol precursor proteins, it is a potential target for inducing the inhibition of HTLV-1 replication. Several potent inhibitors that target HIV-1 protease are used in clinical practice. Previous studies addressed the utility of HIV-1 protease inhibitors (PIs) such as indinavir, saquinavir, nelfinavir, ritonavir, and amprenavir and showed that none of the HIV-1 PIs were effective against HTLV-1 protease (Bagossi et al. 2004; Kadas et al. 2004; Maegawa et al. 2004), most likely because HTLV-1 protease is quite different from HIV-1 in size and amino acid sequence. Recently, small compounds against HTLV-1 protease were designed and shown to be effective at low concentrations, suggesting that they are good candidates for anti-HTLV-1 therapy (Nguyen et al. 2011a, 2011b). The efficacy of the HTLV-1 protease-specific inhibitors warrants further study.
The Principles of Therapy for HIV-1 Infection
Thomas R. O’Brien in Chemokine Receptors and AIDS, 2019
The availability of protease inhibitors, a class of drug that interferes with the HIV-1 protease gene, opened up new treatment options for combination antiretroviral therapy, as protease inhibitor-containing regimens were instrumental to the development of potent antiretroviral regimens. Protease inhibitors that are approved for use in the United States include saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, and lopinavir (57). Single or dual protease inhibitor regimens are often prescribed with combinations of NRTIs or an NNRTI, with the goal of achieving maximal suppression of viral replication through inhibition of two separate viral enzymes. Protease inhibitors inhibit or induce hepatic P450 enzymes, strongly affecting the metabolism of other medications including other antiretrovirals. This effect on drug metabolism can be used advantageously. For example, several effective combinations of dual protease inhibitors (e.g., ritonavir/indinavir, ritonavir/saquinavir) allow dosing at longer intervals for the separate drugs, with augmented drug levels, because one agent (ritonavir) slows metabolism of the other. Lopinavir, a newer protease inhibitor, was approved for use in the United States in a formulation with ritonavir; in this combination, ritonavir acts to slow metabolism of lopinavir.
Sulfonamide inhibitors: a patent review 2013-present
Published in Expert Opinion on Therapeutic Patents, 2018
Human immunodeficiency virus (HIV) PIs are important in highly active antiretroviral therapy (HAART) to treat patients infected with HIV. HAART has been highly successful in controlling HIV replication and reducing the morbidity and mortality rates of patients with acquired immune deficiency syndrome (AIDS). However, significant adverse side effects are associated with the long-term use of HIV PIs [17]. HIV-1 protease enzyme is a critical protein in the lifecycle of the virus, which catalyzes the proteolytic mechanism of polypeptide precursors into structural proteins and perfect enzymes that are necessary parts of HIV-1. HIV-1 PIs stop the alteration of HIV-1 parts into their mature infectious kind, and hence HIV-1 PIs represent a significant therapeutic mechanism in the therapy of HIV-1 infection. Here, we report the discovery of MK-8718, an HIV-1 PI that contains a new morpholine aspartate binding group (Figure 4). The main peculiarity of this inhibitor is that the morpholine amine undergoes an important interaction with the Asp-25A and Asp-25B acidic residues of the enzyme, in contrast to most of the inhibitor compounds, where a hydroxyl molecule plays this key role [18,19]. The HIV PIs of sulfonamides patent applications were filed by Surleraux et al. [20], who developed JP2011051999 (A), a potent, selective, competitive, and reversible HIV PI (Figure 5).
Kinetic and thermodynamic characterisation of HIV-protease inhibitors against E35D↑G↑S mutant in the South African HIV-1 subtype C protease
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Sibusiso Maseko, Eden Padayachee, Siyabonga Maphumulo, Thavendran Govender, Yasien Sayed, Glenn Maguire, Johnson Lin, Tricia Naicker, Sooraj Baijnath, Kruger Hendrik Gerhardus
Protease inhibitors (PIs) are one class of antiviral drugs that target an essential viral enzyme, HIV-1 protease3–5. The role of HIV-1 protease in the processing of Gag and Gag-Pro-Pol polyproteins into building blocks for individual proteins essential for viral maturation, has made it one of the major targets for drug development6. There are currently nine FDA approved protease inhibitors7, originally designed for type B HIV PR8. These inhibitors represent the most potent anti-AIDS drug reported to date and are essential components of the highly active antiretroviral therapy (HAART)9. HAART is credited with significantly lowering AIDS-related deaths, and is currently implemented to the whole world as the standard care for HIV-AIDS treatment9.
Structural determinants for subnanomolar inhibition of the secreted aspartic protease Sapp1p from Candida parapsilosis
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Jiří Dostál, Jiří Brynda, Lucie Vaňková, Syeda Rehana Zia, Iva Pichová, Olga Heidingsfeld, Martin Lepšík
Understanding the three-dimensional structure of aspartic proteases is a key to successful inhibitor design, as was exemplified in the 1990s for HIV protease in search for anti-AIDS drugs20. Yeast Saps are similar in structure to pepsin-like aspartic proteases21. They are arranged as two domains, consisting mostly of β-sheets, with a spacious substrate-binding cleft between them (Figure 1(A)). Each domain contributes one DT(S)G triad to the active site, with the aspartate residue indispensable for catalysis. The central part of the extended active site is covered by an anti-parallel β-sheet, called flap. Peptidic substrates and peptidomimetic inhibitors span the active-site cavity in an extended conformation, placing their amino-acid side chains P4-P1 and P1′-P4′ into their respective S4-S1 and S1′-S3′ pockets (Figure 1(B)). Sapp1p is an enzyme with wide substrate specificity22 and relatively open substrate-binding cleft23. The entrance to the substrate-binding site is lined with four entrance loops (N-ent loop 1, N-ent loop 2, C-ent loop 1 and C-ent loop 2; Figure 1(A)), which modulate inhibitor affinities. Two disulphide bridges (Cys 47 – Cys 53 and Cys 258 – Cys 292) contribute to the stability of the structure.
Related Knowledge Centers
- Enzyme
- Peptide Bond
- Proteolysis
- Retrovirus
- Virus
- Retroviral Aspartyl Protease
- HIV
- HIV/AIDS
- Group-Specific Antigen
- Pol