In 1987 the FDA approved Zidovudine, the first therapy against HIV which was a nucleoside reverse transcriptase inhibitor. By 1996, department of health and human services (DHHS) and the world health organization (WHO) recommended combining anti-HIV medicines; this combined treatment is called anti-retroviral therapy9.
Anti-HIV drugs are organized into five classes based on the stage of the HIV life cycle they inhibit. As of 2019, there were 28 individual agents and 13 fixed dosed combination drugs targeting viral reverse transcriptase (RT), protease and integrase, as well as the cellular entry co-receptor CCR510.
Thirteen individual agents are reverse transcriptase inhibitors belonging to the nucleoside or nucleotide reverse-transcriptase inhibitors (NRTIs) category which lack 3' hydroxyl group on their ribose or ribose mimic moiety including Emtricitabine11, Lamivudine12, Abacavir13, Di-adenosine, Stavudine, Zidovudine and Zalcitabine which has been discontinued14,15,16 or to the non-nucleoside or nucleotide reverse-transcriptase inhibitors (NNRTIs) which bind into a hydrophobic pocket close to the polymerase active site and inhibit polymerization, including Rilpivirine, Etravirine,Delavirdine, Doravirine,Efavirenz and Nevirapine17.
All anti-HIV drugs are associated with a number of short- and long-term side effects18. Chronic HIV infection is associated with increased risk co morbidities. Lapses in medication adherence can lead to viral rebound and disease progression19 also HIV develops rapidly mutations that affect virus susceptibility to treatment20.
For decades the possibility to use nucleic acids as antiviral therapeutics has been studied. In theory antisense oligonucleotides, ribozymes, DNAymes, and aptamers can trigger sequence specific inhibition of particular mRNA transcripts including the viral genomes. However difficulties with their efficiency, off-target effects, toxicity, delivery and stability halted their development and use in the clinic21.
GEM (gene expression modulator) 91 is a 25-mer phosphorothioate (PS) oligonucleotide complementary to the HIV-1 gag initiation site with multiple inhibitory mechanisms22. The non-sequence dependent inhibition of virus entry and reverse transcription were due to a poly-anionic effect of the PS backbone. GEM 91 intracellular RNase H cleavage was inefficient as its free uptake was almost restricted to endosomal vesicles within the cytosol23. PS oligonucleotides nuclear delivery was efficiently improved with cationic lipids inducing higher antisense activity24.
Hybridon developed GEM-92, a second generation oral phosphorothioate gapmer directed against the gag gene in HIV-1 mRNA maintaining the ability to induce RNA cleavage by RNase H with great protection against nucleases and a higher RNA binding25. However, no second generation and only a single first generation antisense oligonucleotide (Fomiversin), for the treatment of CMV-induced retinitis in AIDS patients, have been clinically approved 26.
With advances that have been made in small RNAs systemic delivery, they may soon be evaluated for use in combination drug therapy27. Examples include the small activating RNAs which are double stranded RNAs able to activate gene expression28, the short hairpin RNAs, RNA decoys and aptamers as well as ribozymes that mediate cleavage29, 30.
It is clear that finding new drugs or virucides against HIV-1 infection and AIDS as well as other viral diseases remains a top priority especially in our recent Corona time.
Our design provides compounds intended to stop cDNA synthesis before or at the R region of HIV-1 clone pNL4-3 (GenBank accession No. M19921.2). they prevent RT from continuing cDNA synthesis from the 3' end as no or small part of the R region is going to be transcribed, the last 3' base in these compounds could be a chain terminating base. It is difficult for RT RNAse H site or nucleases to break these compounds down and continue transcription and synthesis as they are modified to resist breaking in all breakable positions.
All mutations that affect RT, protease, integrase as well as envelop gene can't affect them.as they target the pre-PBS region which is a highly conserved region. Moreover, any possible mutations such as SNPs will not affect them as they are polynucleotides. The suspected lower resistance may allow such compounds to have virucidal activity when a suitable dose is used.
Our compounds have a good stability, water solubility and sequence specificity and could be more improved to be druggable and may constitute a nucleus of a new type of antiviral compounds.