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Antiviral Agents and Rational Drug Design
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
The HIV protease enzyme is an aspartyl protease, which contains an aspartic acid residue in the active site, which is crucial for the catalytic cleavage of peptide bonds. The enzyme is a relatively small protein that can be readily made by synthetic techniques or by cloning and expression in rapidly dividing cells, then isolated and purified in large quantities. Crystallisation of HIV protease is relatively straightforward, hence this enzyme is an ideal target for rational structure-based drug design. From x-ray crystallographic studies, novel inhibiters can be developed to produce promising lead compounds.
The Principles of Therapy for HIV-1 Infection
Published in Thomas R. O’Brien, Chemokine Receptors and AIDS, 2019
Thomas R. O’Brien, Eric A. Engels
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.
Darunavir
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Allen C. Cheng, Ramona Muttucumaru, Suzanne M. Crowe
Darunavir is a peptidomimetic inhibitor of the HIV protease, inhibiting proteolytic activity as well as the first step of HIV-1 protease dimerization (Koh et al., 2007; Hayashi et al., 2014). Dimerization of the subunits of the HIV-1 protease are required for proteolytic activity of the protease.
Signal peptide peptidase: a potential therapeutic target for parasitic and viral infections
Published in Expert Opinion on Therapeutic Targets, 2022
Christopher Schwake, Michael Hyon, Athar H. Chishti
For example, Chagas’ disease suffers from noncompliance of standard drugs due to the side effects and diminished effectiveness against chronic infection. HIV protease inhibitors are taken for patients’ entire lifetime owing to their tolerability and effectiveness. The usage of HIV protease inhibitors as another treatment option for parasitic diseases should be considered given the limitations of noncompliance and cost in preventing millions of people from achieving effective therapy. Although long-term usage of HIV protease inhibitors is tolerated by HIV patients, attention should be paid for the inhibition of cytochrome P450 by several such inhibitors [92,93]. Development of parasite-specific SPP inhibitors is a wide-open avenue of future research, which is unlikely to be hindered by technological or methodical limitations. Nonetheless, the major technical challenge for the development of novel SPP inhibitors remains with the differential specificity of these compounds against the pathogen versus host target proteases.
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.
Drug-induced Uveitis in HIV Patients with Ocular Opportunistic Infections
Published in Ocular Immunology and Inflammation, 2020
Ilaria Testi, Aniruddha Agarwal, Rupesh Agrawal, Sarakshi Mahajan, Alessandro Marchese, Elisabetta Miserocchi, Vishali Gupta
Over 25 antiretrovirals have been US FDA approved for combination antiretroviral therapy (CART). Recent guidelines have endorsed treatment strategies for early CART initiation to reduce possible transmission and long-term morbidity and complications. With patients remaining on the same CART regimen for prolonged duration, it is increasingly important to individualize CART to maximize efficacy and also to understand the systemic including ocular side effects of some of these medications. Genetic variants that affect drug-metabolizing enzymes may influence pharmacokinetics (PK) and pharmacodynamics (PD) of CART, thereby influencing its efficacy and side effect profile. Likewise, pharmacogenomics relationships have been proposed for many HIV-1 protease inhibitors, but results have been inconsistent and clear efficacy relationships have not been established.