Anti-HIV Integrase Inhibitors as New Candidates for the Treatment of COVID-19: A Narrative Literature Review

2021 ◽  
Vol 19 ◽  
Author(s):  
Sofia Salari ◽  
Hedyieh Karbasforooshan ◽  
Hesamoddin Hosseinjani
Keyword(s):  
Treatment Options ◽  
World Health ◽  
Health Concern ◽  
Strand Transfer ◽  
Hiv Integrase ◽  
Integrase Inhibitors ◽  
Curative Therapy ◽  
Narrative Literature Review ◽  
Hiv Drugs ◽  
Anti Hiv

Background: The initial reports of a contagious novel Severe Acute Respiratory Syndrome – Coronavirus-2 (SARS-CoV-2) were proclaimed by Wuhan, Hubei province, China. This pathogen quickly became a health concern due to the World Health Organization's (WHO) alarm of its pandemic essence. Hence, there is an urgent need for efficacious and curative therapy against COVID-19. Objective: Theoretically, repurposing anti-viral drugs, specifically HIV treatments, could help the urgent need for treating COVID-19 due to the structural similarities of their critical enzyme substrates. Integrase inhibitors are a category of anti-HIV drugs that inhibit integrase strand transfer. In this review, we investigate the binding affinity and stability of raltegravir, dolutegravir, bictegravir, and elvitegravir in interactions with crucial enzymes of coronavirus. Methods: A literature search was conducted using scientific databases such as Web of Science, Medline (PubMed), Scopus, Google Scholar, and Embase from commencement to September 2020. The most relevant articles regarding the potential effects of integrase inhibitors against COVID-19 were gathered. Ultimately, ten original articles related to the searched terms were selected for this narrative review. Results: Apparently, in addition to the recent drugs prescribed to cure SARS-CoV-2, integrase inhibitors are promising drugs for repurposing in COVID-19 treatment. Several studies on raltegravir, dolutegravir, bictegravir and elvitegravir were conducted using virtual screening to guess either they are effective or not. Encouraging results were mostly reported for raltegravir and dolutegravir. Nevertheless, bictegravir and elvitegravir need more investigations. Conclusion: Further experimental and clinical studies of antiviral drugs are necessary to introduce appropriate treatment options for COVID-19.

Synthesis and Anti-HIV Integrase Inhibitory Activity of β-Diketo Derivatives of Mono-Substituted Calix[4]arene

2013 ◽  
Vol 634-638 ◽  
pp. 1112-1115 ◽  
Author(s):  
Zai Gang Luo ◽  
Xue Mei Xu ◽  
Ming Yang Zhang ◽  
Kuai He ◽  
Xiao Mei Zhang
Keyword(s):  
Transfer Process ◽  
Inhibitory Activity ◽  
Strand Transfer ◽  
Hiv Integrase ◽  
Integrase Inhibitors ◽  
Transfer Step ◽  
Derivatives Of ◽  
Anti Hiv ◽  
Hiv 1 ◽  
Micromolar Range

Six β-diketo derivatives of mono-substituted calix[4]arene were synthesized as potential HIV-1 integrase inhibitors and evaluated their inhibition to the strand transfer process of HIV-1 integrase. Their structures were characterized by NMR and HRMS. All the title compounds as potential HIV-1 integrase inhibitors proved to be active in the micromolar range (6.7–37.6 μM) on the strand transfer step.

scholarly journals Characterization of HIV-1 Integrase Gene and Resistance Associated Mutations Prior to Roll out of Integrase Inhibitors by Kenyan National HIV-Treatment Program in Kenya

2020 ◽  
Vol 30 (1) ◽  
Author(s):  
Mabeya Sepha ◽  
Nyamache Anthony ◽  
Ngugi Caroline ◽  
Nyerere Andrew ◽  
Lihana Raphael
Keyword(s):  
Drug Resistance ◽  
Direct Sequencing ◽  
Integrase Inhibitor ◽  
Hiv Treatment ◽  
Strand Transfer ◽  
Hiv Integrase ◽  
Integrase Inhibitors ◽  
Resistance Mutations ◽  
Integrase Gene ◽  
Hiv 1

BACKGROUND: Antiretroviral therapy containing an integrase strand transfer inhibitor plus two Nucleoside Reverse Transcriptase inhibitors has now been recommended for treatment of HIV-1-infected patients. This thus determined possible pre-existing integrase resistance associated mutations in the integrase gene prior to introduction of integrase inhibitors combination therapy in Kenya.METHODS: Drug experienced HIV patients were enrolled at Kisii Teaching and Referral in Kenya. Blood specimens from (33) patients were collected for direct sequencing of HIV-1 polintegrase genes. Drug resistance mutations were interpreted according to the Stanford algorithm and phylogenetically analysed using insilico tools.RESULTS: From pooled 188 Kenyan HIV integrase sequences that were analysed for drug resistance, no major mutations conferring resistance to integrase inhibitors were detected. However, polymorphic accessory mutations associated with reduced susceptibility of integrase inhibitors were observed in low frequency; M50I (12.2%), T97A (3.7%), S153YG, E92G (1.6%), G140S/A/C (1.1%) and E157Q (0.5%). Phylogenetic analysis (330 sequences revealed that HIV-1 subtype A1 accounted for majority of the infections, 26 (78.8%), followed by D, 5 (15.2%) and C, 2 (6%).CONCLUSION: The integrase inhibitors will be effective in Kenya where HIV-1 subtype A1 is still the most predominant. However, occurring polymorphisms may warrant further investigation among drug experienced individuals on dolutegravir combination or integrase inhibitor treatment. 

scholarly journals Antiviral Characteristics of GSK1265744, an HIV Integrase Inhibitor Dosed Orally or by Long-Acting Injection

2014 ◽  
Vol 59 (1) ◽  
pp. 397-406 ◽  
Author(s):  
Tomokazu Yoshinaga ◽  
Masanori Kobayashi ◽  
Takahiro Seki ◽  
Shigeru Miki ◽  
Chiaki Wakasa-Morimoto ◽  
...  
Keyword(s):  
Synergistic Effects ◽  
Integrase Inhibitor ◽  
Culture Conditions ◽  
Strand Transfer ◽  
Hiv Integrase ◽  
Hiv Replication ◽  
Data Set ◽  
Long Acting ◽  
Anti Hiv

ABSTRACTGSK1265744 is a new HIV integrase strand transfer inhibitor (INSTI) engineered to deliver efficient antiviral activity with a once-daily, low-milligram dose that does not require a pharmacokinetic booster. Thein vitroantiviral profile and mechanism of action of GSK1265744 were established through integrase enzyme assays, resistance passage experiments, and cellular assays with site-directed molecular (SDM) HIV clones resistant to other classes of anti-HIV-1 agents and earlier INSTIs. GSK1265744 inhibited HIV replication with low or subnanomolar efficacy and with a selectivity index of at least 22,000 under the same culture conditions. The protein-adjusted half-maximal inhibitory concentration (PA-EC50) extrapolated to 100% human serum was 102 nM. When the virus was passaged in the presence of GSK1265744, highly resistant mutants with more than a 10-fold change (FC) in EC50relative to that of the wild-type were not observed for up to 112 days of culture. GSK1265744 demonstrated activity against SDM clones containing the raltegravir (RAL)-resistant Y143R, Q148K, N155H, and G140S/Q148H signature variants (FC less than 6.1), while these mutants had a high FC in the EC50for RAL (11 to >130). Either additive or synergistic effects were observed when GSK1265744 was tested in combination with representative anti-HIV agents, and no antagonistic effects were seen. These findings demonstrate that, similar to dolutegravir, GSK1265744 is differentiated as a new INSTI, having a markedly distinct resistance profile compared with earlier INSTIs, RAL, and elvitegravir (EVG). The collective data set supports further clinical development of GSK1265744.

Drug Repositioning: A Smart Approach for Combating SARS-CoV-2

2020 ◽  
Vol 18 ◽  
Author(s):  
Supriya Roy ◽  
Suneela Dhaneshwar
Keyword(s):  
Drug Repositioning ◽  
Symptomatic Relief ◽  
Specific Treatment ◽  
Supportive Therapy ◽  
Cellular Level ◽  
World Health ◽  
Structural Proteins ◽  
Virion Release ◽  
Hiv Drugs ◽  
Anti Hiv

: The enigmatic coronavirus outburst on December 31, 2019, originated from Wuhan city of China, is now declared as Coronavirus disease (COVID-19) by World Health Organization (WHO). The causative agent is highly contagious, and its rapid blowout affects almost every country of the world, endangering thousands of lives. Recently, WHO has raised the COVID-19 epidemic threat to the "very high" level. Pathophysiological mechanisms are related to the interrelated functioning of various viral polyproteins, structural proteins as well as non-structural proteins (NSP). These proteins play a crucial role in accelerating pathogenesis by promoting viral replication, viral assembly, and virion release thereby disabling the overall host distinctive immunological system. Presently, there is no specific treatment for COVID-19. Majority of the treatments focus on symptomatic relief and supportive therapy only. Although several drugs have been investigated against coronavirus in numerous clinical trials, only a few exhibited mild-moderate signs of clinical recovery. Drugs that are being repurposed and researched involve an anti-malarial drug, hydroxychloroquine; anti-HIV drugs, lopinavir, Remdesivir alone, or in combination; anti-influenza drugs like umifenovir, favilavir; anti-arthritic baracitinib, and antiinterleukins. Various research articles demonstrated the excellent potential of hydroxychloroquine either alone or in combination with anti-HIV drugs lopinavir, Remdesivir at the cellular level, however exhaustive clinical support and validation are still desirable for repurposing these drugs. Profound identification of cellular targets involved in disease pathogenesis may warrant successful re-profiling of the candidate drugs or their combinations aiming against COVID-19.

Therapeutic potential of indole derivatives as anti-HIV agents: A mini-review

2021 ◽  
Vol 21 ◽  
Author(s):  
Qingtai Chen ◽  
Chongchong Wu ◽  
Jinjin Zhu ◽  
Enzhong Li ◽  
Zhi Xu
Keyword(s):  
Therapeutic Potential ◽  
Treatment Options ◽  
Multidrug Resistant ◽  
Bioactive Molecules ◽  
Indole Derivatives ◽  
Chemical Structures ◽  
Hiv Drugs ◽  
Immunodeficiency Syndrome ◽  
Anti Hiv Agents ◽  
Anti Hiv

: Acquired immunodeficiency syndrome (AIDS), caused by human immunodeficiency virus (HIV), is one of the leading causes of human deaths. The advent of different anti-HIV drugs over different disease progress has made AIDS/HIV from a deadly infection to chronic and manageable disease. However, the development of multidrug-resistant viruses, together with the severe side effects of anti-HIV agents, compromised their efficacy and limited the treatment options. Indoles, the most common frameworks in the bioactive molecules, represent attractive scaffolds for the design and development of novel drugs. Indole derivatives are potential inhibitors of HIV enzymes such as reverse transcriptase, integrase and protease, and some indole-based agents like Delavirdine have already been applied in clinics or under clinical evaluations for the treatment of AIDS/HIV, revealing that indole moiety is a useful template for the development of anti-HIV agents. This review focuses on the recent advancement of indole derivatives including indole alkaloids, hybrids, and dimers with anti-HIV potential, covering articles published between 2010 and 2020. The chemical structures, structure-activity relationship and mechanisms of action are also discussed.

scholarly journals Discovery of drugs that possess activity against feline leukemia virus

2012 ◽  
Vol 93 (4) ◽  
pp. 900-905 ◽  
Author(s):  
Willie M. Greggs ◽  
Christine L. Clouser ◽  
Steven E. Patterson ◽  
Louis M. Mansky
Keyword(s):  
Leukemia Virus ◽  
Treatment Options ◽  
Feline Leukemia Virus ◽  
Drug Classes ◽  
The Us ◽  
Us Fda ◽  
Hiv Drugs ◽  
Toxic Concentrations ◽  
Anti Hiv ◽  
Hiv 1

Feline leukemia virus (FeLV) is a gammaretrovirus that is a significant cause of neoplastic-related disorders affecting cats worldwide. Treatment options for FeLV are limited, associated with serious side effects, and can be cost-prohibitive. The development of drugs used to treat a related retrovirus, human immunodeficiency virus type 1 (HIV-1), has been rapid, leading to the approval of five drug classes. Although structural differences affect the susceptibility of gammaretroviruses to anti-HIV drugs, the similarities in mechanism of replication suggest that some anti-HIV-1 drugs may also inhibit FeLV. This study demonstrates the anti-FeLV activity of four drugs approved by the US FDA (Food and Drug Administration) at non-toxic concentrations. Of these, tenofovir and raltegravir are anti-HIV-1 drugs, while decitabine and gemcitabine are approved to treat myelodysplastic syndromes and pancreatic cancer, respectively, but also have anti-HIV-1 activity in cell culture. Our results indicate that these drugs may be useful for FeLV treatment and should be investigated for mechanism of action and suitability for veterinary use.

In search of second-generation HIV integrase inhibitors: targeting integration beyond strand transfer

2009 ◽  
Vol 1 (7) ◽  
pp. 1259-1274 ◽  
Author(s):  
Arnout RD Voet ◽  
Marc De Maeyer ◽  
Zeger Debyser ◽  
Frauke Christ
Keyword(s):  
Second Generation ◽  
Strand Transfer ◽  
Hiv Integrase ◽  
Integrase Inhibitors ◽  
Hiv Integrase Inhibitors
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