Below, I present a path to potentially and effectively treat COVID-19 at the pre- exposure and the post-infection stages. A review of the literature indicates that, in the absence of an effective vaccine, no single medication currently has been found to effectively combat SARS-Cov-2. Here, I present a review of the life cycle of COVID-19, including binding and entry mechanisms, translation and replication of the viral genome, and viral assembly and egress, and the current treatment options for COVID-19. Because SAR-CoV and Sars-CoV-2 use multitudinal avenues for entry and egress, coupled with error-prone replication systems that provide avenues to generate quasispecies and escape mutants to monotherapies, I propose here the simultaneous and combinatorial inhibition of these myriad avenues of entry, viral replication and egress, in minimal most effective drug combinations (MMEC) to achieve effective therapeutic synergy to combat COVID19.


 In December 2019, a new form of viral disease presenting with severe acute respiratory syndrome similarly to SARS was announced (1). It was quickly determined that the new SARS-like acute respiratory syndrome was indeed caused by a coronavirus, hence it was named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and WHO named the disease COVID-19 (2). Analyses showed that SARS-CoV-2 is also a beta-coronavirus, with a single (+)-strand RNA genome of approximately 30 kb and sharing 79% overall identity with SARS-CoV. SARS-CoV-2 joins six previously known coronaviruses to cause disease in humans (3). The disease caused by SARS-CoV-2 is now a global pandemic with over 1.8 million persons infected worldwide to-date. Mortality is age-stratified with mortality increasing with age (4) and COVID-19 patients presenting underlying conditions are at greater risk. Presently, there are no drugs available to treat any of the human coronavirus or zoonotic coronaviruses. Thus, there is an urgent need to repurpose approved drugs to treat the pandemic.

Other reviews have focused on single agents, but since SAR-CoV and Sars-CoV-2 use myriad mechanisms for entry and egress, coupled with error-prone replication systems that effectively generate escape mutant(s) to monotherapies, we propose here the simultaneous and combinatorial inhibition of these myriad avenues of entry, viral replication and egress, via therapeutic synergy, to maximize treatment efficacy and minimize chances of generating resistant progeny. This review focuses on the minimally most effective combination for strategic inhibition of SARS-Cov-2 based on the mechanism of action of the available repurposed and investigational drugs as well as their significant side effects. 

Life Cycle

The life cycle of coronaviruses (CoVs) has been extensively studied and reviewed (5, 6). Here, I review CoV life cycle focusing on viral and cellular products, processes and events to identify and highlight suitable targets for therapeutic intervention. Of special significance to the COVID-19 pandemic is the multitudinal entry mechanisms coronaviruses use to gain entry into cells. CoVs enter cells through receptor mediated endocytosis (7, 8, 9), direct membrane fusion (10, 11),  antibody  mediated  enhanced  viral  entry  (ADE)  (12,  13,  14,  15, 16), macropinocytosis (17, 18, 19) and/or Spike protein-mediated syncytia access (10, 11, 20). Since RNA viral populations comprise a quasispecies, consisting of mutation-generated multiple variants centered around a master sequence (21), it  is conceivable that depending on viral variants or cellular target and conditions, SARS-CoV-2 may adopt one or multiple entry mechanisms to gain access into a cell. Each entry mechanism has implications for treatment.

(A)  Binding, Entry and Uncoating

(i) Entry Mechanism 1: The most widely reported mechanism for entry is receptor mediated entry using angiotensin converter enzyme 2 (ACE2) for SARS- CoV and SARS-Cov-2 (5, 22, 23, 24, 25) and dipeptidyl peptidase-4 (DPP4) for MERS-CoV, the coronavirus that causes Middle East respiratory syndrome (6, 26, 27). Binding of coronaviral Spike protein to the cellular receptor ACE2 potentiates the Spike protein for cleavage by cathepsin L (9, 7, 10, 28) and subsequent activation by a cell surface transmembrane protease serine 6, TMPRSS (29, 30) for endocytosis. Following endocytosis, the virus fuses and uncoats in Niemann-Pick Compartment1-positive endolysosomes (31) after which SARS-CoV releases its positive (+) strand RNA genome into the cytosol for translation (32).

(ii) Entry mechanism 2: SARS-Cov-2 may also enter cells via direct viral fusion to cellular membranes similar to other CoVs (10, 11), a process mediated by activating cellular proteases, which include the transmembrane serine protease, TMPRSS in the case of SARS-Cov-2 (33). Upon fusion, the virus uncoats and releases its genomic cargo in the cytosol for replication (25, 34, 35, 36, 37, 38).

(iii) Entry mechanism 3: Coronaviruses also exploit antibody-mediated enhanced viral entry (ADE) to enter In ADE, exposure to non-neutralizing antibodies produced against prior non-lethal coronavirus infections provide a gateway for the chronologically ultimate Coronavirus to enter bystander cells (12, 13, 14, 15, 16). ADE is mediated by surface-expressed Fcγ molecules (13), and enables co-option of macrophages and dendritic cells to spread CoVs. ADE contributes to viral pathogenesis (39, 40). ADE mediated entry also traverses via endosomes and are blocked by compounds that raise endosomal pH (41, 42, 43).

(iv) Entry mechanism 4: Similar to other infectious pathogens including protozoa, bacteria, and other viruses, coronaviruses including SARS-CoV exploit macropinocytosis to evade and invade the host immune system (17, 18, 19, 44, 45, 46). Macropinocytosis proceeds via an endocytic pathway (18, 44, 45, 46).
(v) Entry mechanism 5: Spike-protein mediated syncytia formation is another mechanism through which CoVs can gain access to bystander cells. In this mechanism, coronavirus Spike protein, incorporated or unincorporated into virus, serves as a bridging molecule and causes infected and non-infected cells to fuse together into giant cells (47, 48, 49). The virus is thus able to penetrate hitherto naïve cells. Syncytia formation occurs independently of endocytosis. 

Binding-Entry-Uncoating Treatment options: Where possible, the ideal treatment regimen to effectively curtail Coronavirus entry will simultaneously prevent and/or (i) inhibit receptor mediated endocytosis, (ii) inhibit direct viral fusion to cellular plasma membrane, (iii) inhibit antibody dependent enhanced viral entry, (iv) inhibit syncytia formation and (v) inhibit macropinocytosis. The unifying cellular machinery that links each of the preceding entry mechanisms above, except for syncytia formation, is the endosome. In each case, the endosome must be acidic for the indicated entry mechanism to be productive. Consequently, and barring syncytia-mediated entry, compounds and/or medications that raise the pH of endosomes from acidic to basic levels are apt to inhibit SARS-Cov-2 entering target cells via the entry mechanisms above.

A number of clinically approved medications that elevate endosomal pH have been proposed as treatment for COVID-19, in particular, chloroquine and hydroxychloroquine (50, 51). While shown to be effective in the reported tests,chloroquine and hydroxychloroquine induce severe allergies and arrhythmia that could conceivably complicate their effectiveness in treating COVID-19 in significant global populations (52, 53, 54, 55).
Azithromycin is a lysosomotropic antibiotic that elevates endosomal pH and inhibits virus entry (56, 57, 58, 59, 60) and therefore provide an alternative to chloroquine and hydroxychloroquine in treating COVID-19, irrespective of a population’s allergic response to the latter. Azithromycin, being also antiinflammatory and attenuator of IL-8 and GM-CSF production in primary bronchial cells, may provide additional protection from immune-pathogenesis and inflammation when used to treat COVID-19 (60).

The lysosomotropic agents referenced above may attenuate or block virus entry at the endosomal level, but viral entry into bystander cells mediated by syncytia formation can still result in virus spread, massive cytopathic effects and disease progression, since syncytia formation occurs independently of the endosomal pathway. Indeed, some CoVs including MERS-CoV, employ endosome independent and protease-inducible syncytia formation to enter cells (46, 47, 48). Additionally, even if viral assembly is blocked pharmacologically, unincorporated coronavirus Spike protein can still enhance syncytia formation (9), a process that provides an additional mechanism for CoVs in general and, SARS-Cov-2 in
particular, to enter bystander cells. This would conceivably allow viral pathogenic and immune evasion factors to still enter bystander cells and cause disease.

Spike-induced syncytia formation could be the basis for the extreme hypoxia observed during infection by SARS-CoV/SARS-Cov-2, as it leads to loss of lung orcardiac function (61, 62). Hypoxia upregulates VEGF and VEGFR expression in blood vessels and leads to fluid extravasation (1, 63, 64). Particular attention should be focused on syncytia formation, as a previously unrecognized significant contributor to coronavirus, and in particular SARS-Cov-2 infection and pathogenesis.

Together with ACE2, the cell surface transmembrane serine protease, TMPRSS, mediates SARS-Cov-2 entry into cells and potentiates spike-mediated syncytia formation. TMPRSS is inhibited by Camostat, a clinically proven protease inhibitor, leading to abrogation of syncytia formation (33).

Summary Treatment Options for SARS-Cov-2 Entry:.

From the foregoing (narrative/discussion/mechanism of COV19 entry), and attentive to the known side effects of chloroquine including allergies and cardiac arrhythmia, we propose either (i) Azithromycin/Camostat or (ii) Chloroquine/Azithromycin/Camostat combination therapies to inhibit or block all documented avenues for SARS-Cov-2 cell entry.

(B) Translation and processing of viral genome
Extensive reviews on coronavirus replication have been published (6, 65, 66, 67,8, 69) and will not be reprised here. Briefly however, following entry, uncoating and release of viral genome into the cytoplasm occurs, and viral polyproteins ORF1a and ORF1b (encoding non-structural proteins) and structural proteins are translated from the positive strand viral RNA genome with ORF1b resulting from -1 ribosomal frameshift (65, 69).Here, we will focus on 3 critical virally-encoded proteins: (i) RNA-dependent RNA polymerase (RdRp), (ii) papain-like protein (PLpro) and (iii) ExoN which are critical for the productive infection and pathogenesis of COVID-19, and can be readily targeted by repurposeable approved medications.

(i) RdRp
RNA-dependent RNA polymerase (RdRp) is the virally encoded nucleoside polymerase that incorporates nucleosides into nascent genomic and sub-genomic RNA chains (65). RdRp is conserved among Coronaviruses and absolutely required for all coronaviral replication (69, 70). The replicase-transcription machinery consists of many proteins, however, with the core comprising an integrated complex of RdRp, nsp7 and nsp8 together with nsp14 (ExoN) (71). RNA-dependent RNA polymerases are error-prone and mis-incorporate nucleosides in the order of 10-4 per nucleotide copied per round of transcription (72) resulting in viral quasispeciation (73). Thus, during replication, RNA viruses readily generate escape mutants to selective pressures, be the selective pressure vaccine, host immune response, or pharmacological (74, 75). The genetic diversity that ensues within a quasispecies contributes to pathogenesis (76, 77, 78). Viral quasispecies can increase virulence or immune evasion (79), complicate vaccine development (80, 81, 82) and result in failure of monotherapy (83).

RdRp infidelity by itself could potentially be exploited therapeutically using drugs that introduce lethal and/or chain-terminating mutations into the viral genome. However, the presence of the 3’-5’ exonuclease proof-reading activity of nsp14 (ExoN) in the RNA-synthesizing machinery assures that any therapy targeting CoV RNA synthesis must disable both RdRp and ExoN simultaneously, since the latter will excise the incorporated nucleoside(s) that introduce the lethal mutations. A clinically approved drug, namely Ribavirin (84, 85, 86) and Remdesivir (87, 88,89, 90), target RdRp. Ribavirin targets RdRp but not ExoN while Remdesivir targets and inhibits both RdRp and ExoN (86). Targeting, or not targeting ExoN,could have therapeutic significance as detailed below.

(ii) ExoN (nsp14)
Nonstructural protein 14 (ExoN) encodes bifunctional activities and is essential forviral replication (91). The N-terminal domain functions as a proofreading and DeDDh class 3’-5’ exonuclease activity that ensures genomic fidelity via prevention of lethal mutations (91, 92). The C-terminal domain of ExoN functions as a (guanine-N7)-methyltransferase (N7-MTase) for mRNA capping (93). Both enzymatic activities of ExoN are structurally and functionally integral to the viral RNA-synthesizing machinery. Coronaviruses that retain the proofreading 3’-5’ exonuclease activity are resistant to lethal mutagenesis; coronaviruses that lack the proofreading activity are susceptible to lethal mutagenesis (91). It is important to note that not suppressing both RdRp and ExoN activities may result in the emergence of even more genetically stable and robust escape progeny viruses (94, 95, 96). To be effective, therefore, a therapeutic that targets SARS-Cov-2 RNA synthesis must target both the RNA-dependent RNA polymerase (RdRp) and also the proofreading function integrated into the RNA synthesizing machinery in ExoN. As noted above, Remdesivir targets both RdRp and ExoN (89, 90, 91) and fulfills the properties needed in an effective anti-SARS-Cov-2 RNAsynthesizing therapeutic. Summary Treatment Options for SARS-Cov-2 RNA synthesis: From the foregoing, we propose Remdesivir to target both SARS-Cov-2 RNA synthesis and proof-reading functions.

(iii) PLpro
SARS-CoV PLpro is a multifunctional protein embedded within the multidomain nsp3 polyprotein localized to ER membranes (97, 98). Majority of the nsp3 omains, including the catalytic domain of PLpro, is cytosolic where they partake in essential activities relevant for viral replication and/or immune evasion (99, 100). When it is acting as a cytosolic papain-like protease, PLpro catalyses cleavage and release of mature non-structural proteins nsp1, nsp2 and nsp3 from the viral polyprotein (101, 102). Polyprotein processing by PLpro is co-translational. Indeed, ORF 1a and 1ab polyproteins are not detected during infection, presumably because they are processed co- and post-translationally into intermediate and mature proteins by PLpro and the cysteine proteinase, CLpro, in nascent polyproteins (102). Upon processing of ORF1a polyprotein, PLpro, together with nsp4, participates in the assembly of virally-induced cytoplasmic double-membrane vesicles necessary for viral replication.

As a deubiquitinatase (DUB) and a deISGylatase (103, 104, 105, 106, 107, 108), PLpro processes both ‘Lys-48’- and ‘Lys-63’-linked polyubiquitin chains from cellular substrates and thereby antagonizes innate immune induction by interferon gamma. Via its effects in IFNgamma, PLpro blocks the phosphorylation, dimerization and subsequent nuclear translocation of host IRF3. PLpro also prevents host NF-kappa-B signaling (109, 110). Together, these additional activities in PLpro aid coronaviruses to evade the host innate immune responses and contribute to virulence (111, 112).

The importance of PLpro (and nsp1-4) in CoV replication and virulence was demonstrated during the successful adaptation of Murine Hepatitis Virus, a coronavirus, to Syrian baby hamster kidney (BHK) cells. The cross-species adaptation resulted in variants that gained the ability to cross species barriers to be able to efficiently grow in murine, hamster, human, and primate cells (113). Concomitant with the successful adaptation was the appearance of multiple, possibly, species-adapting mutations in pp1a, particularly in nsp3 (PLpro) and sp4 (113). A review of the literature shows that Disulfiram, an approved alcohol aversive drug, may have broad-spectrum anti-CoV PLpro activity since it has been demonstrated to inhibit MERS-CoV PLpro allosterically and SARS-CoV PLpro competitively (114, 115, 116).

Summary Treatment Option for SARS-Cov-2 PLpro:

As a multifunctional, polyprotein-processing, mutably adaptive, immune-evading inducing virulence factor, PLpro presents a significant therapeutic target. Disulfiram is proposed as the therapeutic for PLpro.

(C) Viral Assembly and Egress
Progeny CoVs assemble at the endoplasmic reticulum Golgi intermediate compartment (ERGIC) membranes and bud and egress from cells in cargo vesicles (116, 117, 118, 119). Specifically, coronaviruses bud exclusively into the ERGIC (119). SARS-CoV egress depends strongly on three structural viral proteins: M, E, and N. It has been established that E localizes primarily to the ER and Golgi complex where it participates in the assembly, budding and intracellular trafficking of infectious virions (120, 121, 122). Assembly of Spike protein into coronavirus particles is mediated by the carboxy-terminal domain of the spike protein (123). Once in the lumen of ER-Golgi intermediate compartment (ERGIC), infectious virions make their way through the host secretory pathway to be exocytosed, ultimately, from the infected cell (124).

The primacy of ERGIC in CoV assembly, budding and egress, together with the large arsenal of approved drugs that target different aspects of ERGIC function make the ER-Golgi compartment a desirable system to investigate for anti-CoV treatment. Strategically, the therapeutic intervention will inhibit a process, event or protein that is absolutely critical for the viral life cycle. Alternatively, the intervention will inhibit each critical step of the viral life-cycle that occurs within ERGIC, namely, assembly, budding and trafficking. Golgi pH, ion and redox homeostasis govern protein sorting, assembly and trafficking (125, 126). These processes that occur at acidic pHs (127, 128, 129) could be inhibited by chloroquine (130). An interrogation of a library of 640 FDA-approved drugs identified chloroquine-related quinacrine, as one of the drugs that disrupted secretory protein transport of diverse cargos (131).

That lysosomotropic agents such as chloroquine and Azithromycin would individually target both CoV entry and uncoating on the one hand and, on the other hand, CoV assembly, trafficking and egress at the ERGIC, has important implications for anti-CoV therapies: the same drugs might be used to block endosome-mediated CoV entry and endolysosomal-mediated CoV egress.

As indicated earlier, however, CoVs could also potentially exit an infected cell via another mechanism, namely, syncytia formation, wherein the spike protein, virusincorporated or not, could bridge adjacent cells to form giant syncytia and allow CoVs access to what would have been naïve bystander cells. Syncytia formation occurs when viruses are able to directly fuse at the cellular surface without the need for endocytosis, since syncytia formation is independent of endocytosis and is pH-independent (47). Thus, treatment with only lysosomotropic drugs to combat CoV entry-egress still leaves the virus with a mechanism to evade the entry/egress targeted therapy. As indicated above, Camostat, the approved pancreatitis drug, inhibits TMPRSS and blocks CoV spike-mediated syncytia formation (33). We propose Camostat would also need to be incorporated in the therapy to inhibit the syncytia bypass mechanism.

Summary Treatment Options for SARS-Cov-2 Assembly and Egress:

From theforegoing, and attentive to Chloroquine allergy, we propose either (i) hloroquine/Azithromycin/Camostat or (ii) Azithromycin/Camostat combination therapies to inhibit or block SARS-Cov-2 assembly and egress.

(D) Summary and Implications for COVID-19 Management

Since RNA viruses readily generate escape mutants to monotherapies, simultaneous administration of combination therapies to target different steps in SARS-CoV-2 lifecycle may help reduce and delay the development of viral resistance, with each drug in the cocktail raising the resistance barrier for the virus. Effective combination antiviral therapies minimize viral replication to undetectable levels and make combinational drug therapy more successful than monotherapies (132).

Multi-target synergy also achieve therapeutic selectivity, with synergistic combinations increasing the number of selective therapies (133). Mindful of reported drug interactions (134, 135), for COVID-19, we propose a combination therapy consisting of either Chloroquine or Azithromycin, with Camostatand Remdesivir as follows:

The Minimum Most Effective Combination (MMEC) of medications needed to contain SARS-Cov-2 viral entry and egress, simultaneously, would appear to be three: Chloroquine or Azithromycin separately, with Camostat combination. With consideration to the adverse reactions to chloroquine, we would recommend the following MMECs:

A)  Azithromycin/Camostat 

  1. For Pre-exposure prophylaxis; COVID19 contact management; Frontline medical
  2. For infected individuals with mild symptoms, with or without chloroquine allergy and no underlying cardiac condition.
  3. For infected individuals with mild symptoms with underlying cardiac conditions.
  4. Chloroquine may be used in combination with Camostat where chloroquine is not contraindicated.

B) Azithromycin/Camostat/ Remdesivir
1) For advanced COVID19 status – where productive infection has occurred, i.e., viral replication has commenced, critical viral proteins have been produced in vivo, shedding is ongoing and progeny virus have commenced spread in situ, we
propose combining the PEP regimen together with Remdesivir (to block further replication).
2). Introduction of Chloroquine and Disulfiram into the regimen must be
closely monitored because of the significant side-effects they evoke.
3). Multidrug tolerability and effectiveness in prophylactic or therapeutic combination will need to be established in randomized control trials to justify their use clinically.
4) Drugs in the respective classes identified herein may be investigated in combination as well.
5). The proposals might be extended to other Coronavirus outbreaks, including  SARS and MERs.

Figure 1: SAR-CoV-2 and Coronavirus Life Cycle and Strategic Grids for Therapeutic Synergy Intervention

1) SAR-CoV-2 or CoV virus life cycle is illustrated in Grid A-1 to A-7.  Stages in SAR-CoV-2/CoV lifecycle for therapeutic targeting are indicated by X: I) Binding, entry and uncoating (Grid A-1 to A-3); II) Replication (Grid A-4 to A-5); and III) Assembly, trafficking and egress (Grid A-6 to A-7).

2A) Entry mechanisms used by SAR-CoV-2/CoV are illustrated in Grid B-1 to B-3.  I) SAR-CoV-2/CoV use five different mechanisms to enter a cell. Four of the entry mechanisms are endocytosis-dependent:  i) ACE2 receptor; ii) Membrane fusion; iii) Antibody-dependent Entry (ADE); and iv) Macropynocytosis (Grid B-2). II) Syncytia is an endocytosis-independent mechanism and is mediated by the CoV spike protein and cell surface TMPRSS serine protease (Grid B-3). 

2B)  COVID19 or CoV’s viral replication and assemby are illustrated in Grid B-4 to B-7I) Once COVID19 or CoVs achieve productive entry and uncoating, viral replication ensues with viral RNA synthesis and proofreading (Grid B-4) and polyprotein processing (Grid B-5).  II) Virus assembly, trafficking and budding proceed in the ER-Golgi intermediate compartment (ERGIC) (Grid B6)  for egress at the plasma membrane or through syncytia formation (Grid B-7).

3) Clinically approved drugs recommended for SAR-CoV-2 therapeutic synergy intervention and their mechanisms are listed in Grid C-1 to C-7. I) Drugs against Cellular Targets. i) Endocytosis-dependent entry proceeds via endosomes and can be blocked by lysosomotropic drugs such as Chloroquine or Azithromycin which act by elevating endosomal pH (Grid C-2).  The same lysosomotropic drugs Chloroquine or Azithromycin block assembly, trafficking and processing at the ERGIC by raising endo-vesicular pH (Grid C-6). ii) Spike-mediated syncytia formation is dependent on cell surface protease TMPRSS and can be blocked by Camostat via inhibition of TMPRSS activity (Grid C-3). Camostat also blocks viral egress mediated by spike-mediated TMPRSS-dependent syncytia (Grid C-7).  II) Drugs against Viral Proteins. Viral encoded RdRp mediates SARS-CoV2/CoV RNA synthesis and its fidelity is provided by ExoN.  Remdesivir inhibits the activities of both RdRp and ExoN (Grid C-4). CoV PLpro partakes in viral polyprotein processing and can be inhibited allosterically or competitively by Disulfiram (Grid C-5).

(E) Other Matters
1. Multitudinal entry assures that blocking any one entry mechanism, such as ACE2-mediated entry alone, may reduce infection rate but ultimately be ineffective since the other entry mechanisms could provide bypass mechanisms for SARS-Cov-2 to enter cells.
2. Multitudinal entry also assures that re-infection of an individual can occur
even after initial viral clearance since multiple entry mechanisms accentuate reinfection and superinfection.

3. Antibody-mediated entry has significant implications, namely:
a). Previous exposure to non-lethal, immune-cleared CoVs  could predispose an individual to more extensive COVID-19 virulence: ADE exposes Fcgamma-bearing dendritic cells and macrophages to infection and/or simultaneously co-opts them to spread the virus further afield to other tissues (heart, liver, kidneys, intestines and eyes) which will ultimately be attacked by SARS-Cov-2 even if the lungs somehow escaped cytopathy.

b). The combination of ADE with dual egress, particularly  syncytia formation, assures rapid devastation of primary SARS-Cov-2 target organs, particularly the lungs, or whichever organs they may be.
c) A patient’s previous history of exposure to nonlethal CoV infections may provide an insight into the severity of disease progression and may help explain age-stratification of COVID-19 mortality. The same could help explain “outliers” of age-stratified COVID-19 mortality.
d). A test that distinguishes exposure to other CoVs from exposure to SARS-CoV-2 may be a predictor of COVID-19 disease severity and possible outcome.
4. The error prone nature of RdRp, even in the presence of functional ExoN,  assures there will be polyspeciation with mutations that could confer resistance to any single COVID-19 (mono)therapy. We propose that combinatorial therapy, therefore, as the best treatment option for COVID-19.


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ACKNOWLEDGMENTSWe express sincere thanks to Dr. Charlene F. Barroga for discussions and, to her and Dr. Tony Hunter (Salk Institute) for critical review of the manuscript.  

CONFLICT OF INTEREST DECLARATION:  The author declares no conflict of interest.

ACCREDITATION STATUS: Thrivus Institute for Biomedical Science and Technology is undergoing program review by the National Accreditation Board of Ghana

NONMEDICAL USE STATEMENT: The therapeutic agents identified herein, and combinations thereof, are for research purposes only. They are not prescriptions and are not to be taken as self-medication for the treatment or cure for any disease or sickness. Contact your health-care provider for medical advice and care.