Skin disorders in AIDS, immunodeficiency, and venereal disease
Rashmi Sarkar, Anupam Das, Sumit Sethi in Concise Dermatology, 2021
The first effective treatment for AIDS was zidovudine (AZT, azidothymidine), a reverse transcriptase inhibitor, given at 500–1500 mg per day in four to five divided doses. The drug slows down the progress of the HIV infection but comes nowhere near eliminating the viral infection. Unfortunately, it causes nausea, malaise, headache, and rash as well as many other side effects. Several other classes of antiretroviral drugs are now available. Other nucleoside analogue reverse transcriptase inhibitors include lamivudine, nevirapine, stavudine, delavirdine, and efavirenz. Other classes of drugs in use include protease inhibitors and non-nucleoside reverse transcriptase inhibitors. Optimal regimens now usually consist of at least three drugs from two classes of antiretroviral agents. The newer antiviral drugs include enfuviritide (fusion inhibitor), maraviroc (blocks the entry of virus into cell by blocking the CD4 protein), and the integrase inhibitors (raltegravir, dolutegravir). Although promising, trials are going on to assess the efficacy of these drugs.
HIV Integrase Inhibitors
Satya Prakash Gupta in Cancer-Causing Viruses and Their Inhibitors, 2014
Studies to understand critical events required for viral replication revealed several key targets for developing anti-HIV drugs, including three crucial viral enzymes: integrase (IN), protease, and reverse transcriptase (De Clercq 1995; Fauci 1988). Currently, 26 drugs have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIV infection, and many new drugs are in clinical trials (Belavic 2013; De Clercq 2009; Neamati 2011). The approved drugs belong to the following categories: reverse transcriptase inhibitors (12 drugs), protease inhibitors (10 drugs), fusion inhibitor (1 drug), cell entry (CCR-5 co-receptor) inhibitors (1 drug), and IN inhibitors (2 drugs). The most effective approach for the treatment of HIV-infected patients is called highly active antiretroviral therapy (HAART), in which a combination of drugs targeting two or more key steps in the viral life cycle are administered together (De Clercq 2009). However, mutations arising in the HIV genome that confer resistance toward existing drugs in a large number of patients, physiological side effects, and drug toxicity limit the effectiveness of HAART (Mouscadet and Desmaële 2010; Shafer and Schapiro 2008). These issues drive the need to develop new, effective anti-HIV drugs with acceptable tolerability in terms of side effects, toxicity, and mutation profile. Discovery of novel inhibitors that are structurally and/or mechanistically different is required to inhibit viral strains resistant to the approved drugs.
Dolutegravir
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 in Kucers’ The Use of Antibiotics, 2017
The antiviral activity of dolutegravir was additive or synergistic when combined with the integrase inhibitor raltegravir; a nonnucleoside reverse transcriptase inhibitor, such as efavirenz or nevirapine; a nucleoside reverse transcriptase inhibitor, such as abacavir or stavudine; a protease inhibitor, such as amprenavir or lopinavir; the CCR5 co-receptor antagonist maraviroc; or the fusion inhibitor enfuvirtide (Kobayashi et al., 2011). In addition, dolutegravir antiviral activity was not antagonistic when combined with the hepatitis B virus reverse transcriptase inhibitor adefovir or inhibited by the antiviral ribavirin.
Envelope proteins as antiviral drug target
Published in Journal of Drug Targeting, 2020
Jyoti Verma, Naidu Subbarao, Maitreyi S. Rajala
Broad spectrum of entry/fusion inhibitors includes natural products such as griffithsin and squalamine inhibiting number of viruses, including flaviviruses. Another such compound is an indole-derivative arbidol, which inhibits membrane fusion by impending the conformational changes of fusion peptide during virus fusion [59,60]. A selective inhibitor, GS-563253 (HCV II-1) of HCV genotypes 1 and 2 was reported with low nanomolar EC50 preventing the endosomal fusion [61]. A group of researchers established a competitive amplified luminescent proximity homogeneous assay (ALPHAscreen) through which they identified small molecule inhibitors targeting envelope protein mediated membrane fusion of Zika virus [62]. They also report seven lead compounds having potent activity against the closely related dengue virus 2 but not vesicular stomatitis virus G protein which is a class III fusion protein. Chloroquine has been reported to block the expression of VSV glycoprotein G and addition of 50 mg/ml of chloroquine prevented virus induced cell fusion [63]. Since, chloroquine prevents endosomal acidification; it blocks the fusion of the virus with the endosomal membrane. Hence, chloroquine and its analogs have potential for the treatment of endosomal low pH dependent emerging viruses. Small molecule inhibitors with strong fusion inhibitor activity either with plasma membrane or with the endosomal membrane can be successful antiviral drugs.
Emerging small and large molecule therapeutics for respiratory syncytial virus
Published in Expert Opinion on Investigational Drugs, 2020
Harrison C. Bergeron, Ralph A. Tripp
As RSV fusion to host cells is required for infection [59], blocking this initial stage of infection with a fusion inhibitor is an attractive mode of therapy. Presatovir (GS-5806; Gilead Sciences) is an oral fusion inhibitor that blocks pre-fusion protein conformational change [60]. In in vitro studies examining the breadth of protection, a panel of 75 clinical RSV isolates were examined and Presatovir was found to reduce virus replication in all isolates tested [61]. In vitro safety assessment showed that Presatovir exhibited low cytotoxicity in human epithelial type 2 (HEp-2) cells. In healthy human adults challenged with RSV (strain M37) patients treated with Presatovir at day 5 post-infection, or who were RSV PCR positive, had reduced viral loads, decreased mucus weight and lower symptom scores [62]. Recent Phase II studies evaluating Presatovir treatment in RSV-positive lung transplant patients [63] and hematopoietic cell transplant recipients [64] did not show treatment improved viral or clinical outcomes. Despite not meeting primary endpoints, it is indicated Presatovir will continue in clinical trials, evaluated in different populations with altered primary endpoints.
The mechanism and pharmacodynamics of 2-((1H-indol-3-yl)thio/sulfinyl)-N-pheny acetamide derivative as a novel inhibitor against human respiratory syncytial virus
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Ningning Cheng, Nan Jiang, Yuanhui Fu, Zhuxin Xu, Xianglei Peng, Jiemei Yu, Shan Cen, Yucheng Wang, Guoning Zhang, Yanpeng Zheng, Jinsheng He
The time-of-addition assay, hence, was carried out to specify replication stage (s) at which 4–49 C and 1-HB-63 (Figure 1) inhibit RSV infection, respectively. As the results shown in Figure 2(A), compared with DMSO (negative control), ribavirin (genome replication stage-targeted inhibitor), RSV604 (N protein inhibitor), and GS-5806 (fusion inhibitor), 4-49 C significantly inhibited virus replication when added at the time points of −1, 0 and 2 h, similarly to the GS-5806 having inhibition activity only when added up to 0 and 2 h. While 1-HB-63 significantly inhibited virus replication when added at the time points of −1, 0, 2 and 4 h. Thus, the results indicated that 4-49 C inhibits virus replication in the initial stage of RSV infection or before entry of the targeted cells, and 1-HB-63 acts in the late stage of RSV infection or after entering the cells.
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