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  • RGDfK Acknowledgments The authors would like to thank member

    2022-07-02

    Acknowledgments The authors would like to thank members of the Department of Discovery Synthesis (DDS) and Biocon-Bristol Myers Squibb Research Center (BBRC) for scaling up key intermediates, analytical team for analytical experiments, lead profiling group for evaluating compounds in an in vitro ADME&T assays and discovery toxicology team for in vivo safety assessment in dogs and rats.
    Introduction Antiretroviral therapy (ART) combines the use of at least three different drugs to treat HIV-1-infected individuals. Since first introduced in 1996, ART has resulted in a great decrease in HIV-related morbidity and mortality and improved the quality of life of HIV-1 infected patients. Currently, there are 29 Food and Drug Administration (FDA)-approved anti-HIV drugs, which are classified into six different groups based on their mode of action. However, HIV can develop resistance to all of these anti-HIV drugs. Integrase strand transfer inhibitors (INSTIs) are the latest class of anti-HIV drugs. INSTIs inhibit the HIV-1 integrase strand transfer step to block the integration of HIV viral DNA into host cell chromosomal DNA. To this date, three FDA-approved INSTIs are in use in the clinic: raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG). These three INSTIs are highly effective in both treatment-naïve patients as well as in treatment-experienced individuals who may possess multi drug resistance to other drug RGDfK (Park et al., 2015). Currently, five drug formulations containing either an INSTI alone (Isentress (Merck & Co.), Tivicay (ViiVHealthcare), or Vitekta (Gilead Sciences)), administered with two nucleos(t)ide drugs or INSTIs co-formulated with N(t)RTIs (Stribild (Gilead Sciences) and Triumeq (ViiVHealthcare)) are used in clinical practice. HIV can develop resistance to RAL or EVG relatively rapidly both in vitro and in patients who are experiencing treatment failure (Geretti et al., 2012, Mesplede et al., 2013, Quashie et al., 2013, Grobler and Hazuda, 2014). The genetic barrier to resistance is referred to a sufficient number of mutations required by the virus to overcome the anti-HIV activity of a drug regimen. RAL and EVG have a relatively low genetic barrier to resistance, since only 1 or 2 mutations in HIV-1 integrase are capable of greatly reducing HIV susceptibility to either of them. Cross-resistance between RAL and EVG has also been observed. However, DTG, a second generation INSTI, has shown resistance patterns that are different from those seen with RAL or EVG. Although limited cross-resistance exists among DTG, RAL and EVG, DTG is the only anti-HIV drug against which resistance mutations have not developed in treatment-naïve patients in clinical practice (Underwood et al., 2013, Mesplede and Wainberg, 2014, Fourati et al., 2015). However, HIV-1 has a nature of extensive and dynamic genetic diversity that results in different variants. These variants, classified into distinct molecular subtypes and/or recombinant forms, display an uneven global and regional distribution (Santoro and Perno, 2013). Due to its diversity, HIV-1 variants are usually classified into four major phylogenetic groups: group M (main), group O (outlier), group N (non-M/non-O), and group P. Group M is the major variant, accounting for >97% of all HIV-1 epidemic worldwide (Tebit and Arts, 2011) and it can be further subclassified into 9 genetic subtypes or clades (A to K), mainly based on the subgenomic regions of individual genes. With improved sequencing methods such as deep sequencing, the number of known viral variants has greatly increased worldwide. Currently, HIV-1 phylogenetic classifications are based either on nucleotide sequences of HIV-1 subgenomic regions such as gag, pol, and env or on full-length genome sequence. This last approach has revealed some intersubtype recombinant forms that are believed to have originated in individuals concomitantly infected with viruses of two or more subtypes. When an identical recombinant virus is characterized by full-length genome sequencing in at least three epidemiologically unlinked individuals, it can be designated as a circulating recombinant form (CRF). Recent studies have shown that the most prevalent HIV-1 genetic forms are subtypes A, B, and C, especially subtype C, that accounts for almost 50% of all HIV-1 infections worldwide. Subtype A viruses are predominant in Africa and in some eastern European countries. Subtype B is the main genetic form in Europe, the Americas, and Australia and in several countries of Southeast Asia, northern Africa, and the Middle East and among South African and Russian homosexual men (Buonaguro et al., 2007).